Open access peer-reviewed chapter

A New Insight into the Development of Novel Anti-Cancer Drugs that Improve the Expression of Mitochondrial Function-Associated Genes

Written By

Fumiaki Uchiumi, Jun Arakawa, Yutaka Takihara, Motohiro Akui, Hiroshi Hamada and Sei-ichi Tanuma

Submitted: 15 March 2017 Reviewed: 20 September 2017 Published: 20 December 2017

DOI: 10.5772/intechopen.71095

From the Edited Volume

Mitochondrial Diseases

Edited by Eylem Taskin, Celal Guven and Yusuf Sevgiler

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Recent analyses of the whole genome sequencing data enable us to predict cancer incidence for healthy people at present. In addition, metabolome analyses rediscovered that “cancer is a metabolic disease”. Importantly, it has been suggested that mitochondrial dysfunction might precede the metabolic change. In this chapter, we would discuss if “cancer is a transcriptional disease”. Analyzing 5′-upstream non-protein-encoding regions of the human mitochondrial function-associated genes, we speculate that mitochondrial functions could be recovered or improved at a transcriptional level. In the near future, novel chemo-/gene-therapies might be applied to treat cancer patient converting cancerous cells into normal differentiated cells.


  • cancer
  • CTCF (CCCTC-binding factor)
  • DNA repair
  • ETS (E26 transformation specific)
  • gene expression
  • GGAA
  • HMGB (High mobility group box)
  • ISG (Interferon stimulated gene)
  • metabolism
  • mitochondria
  • NAD+
  • PARP inhibitors
  • poly (ADP-ribosyl)ation
  • PARP (poly(ADP-ribose) polymerase)
  • transcription
  • transcription factors
  • Warburg effect

1. Introduction

We have already learned that “cancer is a genetic disease”. Recent high-impact research has shown the genomic/genetic differences between cancer and normal cells using methods such as next-generation sequencing [1, 2]. The analysis of the whole genome sequencing data will even enable us to predict the incidence of cancer in healthy individuals [3]. More importantly, recent metabolome analyses have led to the rediscovery that metabolites could be biomarkers for cancer and its development [4]. The “Warburg effect”, which was shown by Dr Otto Warburg over 60 years ago, is the most essential discovery in the field of cancer science [5]. The “Warburg effect” refers to abnormal metabolism in cancer, which mainly utilizes glucose to produce ATP by glycolysis. In this regard, “cancer is a metabolic disease”. This is not only important as an indicator of tumors, but also as one of the essential characteristics of cancer [6, 7]. A number of lines of evidence, including dysregulated TCA (Krebs/Citrate)-cycle progression and the insufficient oxidative phosphorylation in cancer cells, suggest that mitochondrial dysfunction might precede the metabolic change [8]. Thus, “cancer must be a mitochondrial disease”. In this chapter, which focuses on the causative factors that lead to mitochondrial dysfunction, we discuss whether “cancer is a transcriptional disease”. Most of the genes (99%) that encode mitochondria or their function-associated proteins are contained in nuclear genomes [9]. The mitochondrial functions might be recovered or improved at a transcriptional level. In this chapter, we propose the establishment of novel chemo-/gene-therapies with no side effects, to force cancerous cells to regenerate into their normal differentiated state.


2. The relevance of duplicated GGAA-motifs in the 5′-upstream regions of human genes to the regulation of biological events

2.1. The transcription factors that recognize and bind to the GGAA-containing motifs

The most widely known transcription factors (TFs) that selectively recognize the GGAA-core-containing sequences are the ETS (E26 transformation specific) family proteins, which consist of at least 27 members [10, 11]. Moreover, a genome-wide ChIP-seq analysis estimated that the promoter regions of human genes are very frequently occupied by ETS family or GGAA-binding proteins [12]. The duplication of the GGAA-motif could be advantageous to organisms, as it would allow the transcription of various genes to be controlled in a manner that is mainly dependent on the expression profile of the GGAA-binding proteins in the cells [13, 14]. Besides ETS family proteins, several TFs could bind to the motif. For example, some of the duplicated GGAA-motifs would be identical to IFN-stimulated response element (ISRE), the consensus sequence of which is 5′-GGAAANNGAAACT-3′ [15], if one of the Ns was G. The double-stranded sequence, 5′-AACTTT-3′, which is a core binding motif of the IRF1 [16], could be generated if CT was inserted between GGAA and TTCC. Moreover, NF-κB p65 (RELA) homodimer binds to two symmetric sequences, 5′-GGAATTTCC-3′ and 5′-GGAATTCCC-3′ [17]. IRF8 (ICSBP) either positively or negatively regulates transcription through binding to ISRE [18, 19].

Importantly, the ETS family proteins and other TFs cooperatively regulate the expression of various genes. For instance, STAT1 plays a role in the regulation of the expression of interferon (IFN)-stimulated genes (ISGs) with ETS family proteins [20, 21]. Sp1 and Ets1 interact with each other to regulate mouse Npr1 gene expression [22]. The ETS-binding consensus sequence is frequently found with a second ETS-binding sequence and with the Sp1-binding sequence, but not with a TATA element [23], implying the exclusive role of the GGAA- and TATA elements. The human VEGFR1 promoter region, which contains overlapping GGAA-motifs, is also regulated by CREB and EGR-binding elements [24]. Furthermore, the mouse Ppp2r1a gene promoter, which carries duplicated TTCC motifs, is regulated by Creb, Ets1, Ap2 alpha, and Sp1proteins [25]. Thus, multiple elements adjacent to duplicated GGAA-motifs may recruit various TFs to form a pre-initiation complex on the transcription start site (TSS) of TATA-less promoters. The transcription initiation system might be advantageous for a rapid response to stresses in a TATA-independent manner.

2.2. The duplicated GGAA-motifs that are contained in the 5′-upstream regions of immune response factor-encoding human genes

Duplicated GGAA-motifs are found in the 5′-upstream of the ISGs [20, 26, 27]. The GGAA-motifs are also harbored in the IFN-stimulated response element (ISRE)-like sequences [28, 29]. Thus, the duplicated GGAA-motifs near TSSs may play roles in controlling the expression of ISGs. The ISG-encoded proteins include TFs, immune modulators, apoptosis mediators, and anti-viral factors [30]. Previously, the duplicated GGAA-motifs in the regulatory regions of ISGs have been analyzed [31]. We surveyed the 5′-upstream regions in a number of ISGs to find GGAA-motifs within 500-bp upstream from the TSSs [32], and reported that IFNβ-inducible human OAS1 promoter activity is regulated by binding of ELF-1 (which belongs to the ETS family proteins) to a duplicated GGAA-motif, and by its interaction with Sp1 and Rb proteins [33].

Collectively, the majority of the promoter regions from ISGs contain duplicated GGAA-motifs but rarely with TATA element. This suggests that the mechanism by which transcription is initiated differs from that of the house-keeping genes or genes that are essentially required, such as those that encode cell structure components. IFNs, the expression of which should be suppressed under normal conditions, only play important roles when it is necessary to fight against viral infection and oncogenesis. The duplicated GGAA-motifs might have contributed, through evolution, to the development of an immune response at the transcriptional level. In addition, GGAA-binding factors, which are associated with other TFs around TSSs, facilitate the expression of each ISG as appropriate, depending on the different signals that are induced by IFN.

2.3. The duplicated GGAA-motifs in the 5′-upstream regions of the human DNA repair factor-encoding genes

The duplicated GGAA (TTCC) motif is present adjacent to the TSS of the human TP53 gene [34], the expression of which is regulated by IFN-α and β [35]. IRF1 was reported to be a negative regulator of the human TERT promoter in response to IFN-γ [36]. In addition, IRF-5 has been shown to upregulate the expression of DNA repair/apoptosis-associated genes [37]. Moreover, DNA damage initiates an immune response that regulates DNA repair-associated genes [38]. These observations suggest that the immune responses and DNA damage responses might be co-dependent, and that the duplicated GGAA-motifs have important roles in controlling the expression of genes that encode DNA repair-associated factors in response to IFN-induced signals.

It should be noted that the duplicated GGAA-motif is present in the promoter regions of the human Poly(ADP-ribose) polymerase 1(PARP1) [39, 40] and XRCC1 [41] genes. The duplicated GGAA-motifs are present near the TSS of the ADPRHL2 (ARH3) and the ZC3HAV1 genes, which encode mitochondria-localizing poly(ADP-ribose) (PAR) degrading enzyme [42] and an anti-viral RNA-binding protein PARP13 [43, 44], respectively. These findings suggest that the expression of genes encoding single-strand DNA break repair factors is commonly regulated by the duplicated GGAA-motifs.

The promoter activities of the human WRN and TERT genes, both encoding telomere maintenance factors, positively respond to both 2-deoxy-d-glucose (2DG) [45] and trans-resveratrol (Rsv) [46], which are caloric restriction (CR) mimetic drugs that have been shown to prolong the life span of several organisms [47]. The natural compound Rsv upregulates the expression of the HELB gene [46, 48], which encodes DNA replication and DNA double strand break repair-helicase HELB (HDHB) [49, 50, 51, 52]. Moreover, the 5′-regulatory regions of the genes that encode DNA repair factors, such as XPB, RB1, RTEL1, ATR, TP53, and CDKN1A (p21), contain GGAA duplications near the TSS [53]. Several of the DNA repair factors are localized in the mitochondria and may also regulate the mitochondrial functions [53].

2.4. The surveillance of regulatory regions adjacent to the TSSs of human mitochondrial function-associated genes

The surveillance of a human genomic DNA database suggested putative TPA-responsive elements in the 5′-upstream regions of the MRPL32, NDUFB3, NDUFS3, SDHB, and SDHAF2 genes contain GGAA duplication [54]. The duplicated GGAA-motifs are present in the upstream regions of human genes encoding mitochondrial ribosomal proteins and enzymes or components that function in the TCA cycle and oxidative phosphorylation (OXPHOS) [54].

Mitochondrial dysfunction is thought to cause either cellular senescence or oncogenesis [55, 56, 57, 58]. Remarkably, TCA cycle enzymes, fumarate hydratase (FH), and succinate dehydrogenase (SDH) have been suggested as tumor suppressors [59]. Hence, mutations of the TCA cycle factor-encoding genes give rise to abnormal mitochondrial respiration, which is one of the characteristics of tumors and cancer [60, 61]. Mutations of the IDH1 and IDH2 genes have been identified in human brain cancer cells [62, 63]. A recent study demonstrated that the mutation of IDH2 could lead to the generation of sarcoma [64]. Duplicated GGAA-motifs are contained in the upstream region of the NAMPT (NmPRT), encoding a nicotinamide phosphoribosyltransferase that catalyzes the first rate-limiting step of (nicotinamide adenine dinucleotides) NAD+ synthesis from nicotinamide [65, 66, 67]. Depending on the NAD+ level, NAMPT could modulate the TCA cycle, poly(ADP-ribosyl)ation, and sirtuin-mediated de-acetylation [66, 67]. The duplicated GGAA-motifs are present near the TSSs of the human TCA cycle enzyme-encoding ACLY, ACO2, CS, FH, IDH1, IDH3A, IDH3B, SDHAF2, SDHB, SDHD, and SUCLG1 genes [68].

A duplicated GGAA-motif is present in the bidirectional promoter of the PDHX [54], which encodes one of the components of the PDH enzyme to metabolize pyruvate to acetyl-CoA. Aberrant pyruvate metabolism is thought to play a prominent role in cancer [69]. The genomic deletion of ME2, which encodes malic enzyme 2 (an NAD+-dependent malate decarboxylase that converts malate into pyruvate), is found in pancreatic ductal adenocarcinoma [70]. The GGAA-duplication is not only found near the TSSs of the human ME2 gene, but also the MDH2 gene (which encodes NAD+-dependent malate dehydrogenase), suggesting that duplicated GGAA-dependent transcription could affect the metabolism of malate in the mitochondria.


3. The possible roles of metabolic states that can alter transcription profiles

Recently, a study using a CAP-SELEX analysis showed that different transcription factors, such as FOXO1 and ETS family proteins, are mediated by a DNA that contains a GGAA-core motif [71]. As described above, a number of promoters or regulatory regions of human genes that encode immune response-/DNA repair-/mitochondrial function-associated proteins contain overlapping or duplicated GGAA-containing motifs. Thus, the alteration of the profile of the GGAA-motif-binding proteins or their associated protein factors may allow for the control of appropriate cellular responses against viral infection, DNA damage, and oxidative/nutrient/metabolic stress. Importantly, the DNA damage responses affect the transcriptional state [72] through oxidative stress, which is mainly produced by the mitochondria [73, 74]. NF-κB- and p53-dependent transcription, which regulates the expression of the ISGs and DNA repair factor-encoding genes, is also affected by oxidative stress [75]. Thus, metabolites that are mainly produced by respiration or mitochondrial functions may influence the transcription control system [76, 77].

3.1. The transcription profile may be controlled by the NAD+/NADH balance

We have reported that the promoter regions of the human TP53, HELB, and telomere maintenance factor-encoding genes respond positively to Rsv [46, 48, 78]. Rsv not only activates SIRT1, which is an NAD+-dependent deacetylase [79], but also inhibits phosphodiesterase [80]. Importantly, low-dose Rsv activates mitochondrial complex I [81] to upregulate the NAD+/NADH ratio, to induce the expression of duplicated GGAA-motif-driven genes. The transcription of the bidirectional promoter-driven BRCA1/NBR2 genes, which contain a duplication of the GGAA-motif, may be regulated by the NAD+/NADH ratio [82]. Notably, the C terminal-binding protein (CtBP) [83, 84] has a central role in this regulation as a metabolic sensor. Moreover, PARP1 poly(ADP-ribosyl)ates transcription elongation factor NELF to release the paused RNA pol II-dependent transcription [85], suggesting that PARP1 itself contributes to NAD+-sensitive transcription. Recently, it was reported that nuclear PAR can be utilized by NUDIX5 to supply ATP molecules, which are required for chromatin remodeling [86]. Thus, the accumulation of NAD+ molecules or NAD+/NADH ratio-sensitive proteins, including GGAA-motif binding TFs, might affect the transcription of ISGs/DNA repair/mitochondrial function-associated genes in response to metabolic stress.

It should be noted that PARP activity is upregulated in tumors and cancer cells [44]. Because the duplicated GGAA-motifs are present in the 5′-upstream regions of the human PARP and PARG genes [40], subtle changes in the quality/quantity profile of the GGAA-binding TFs may modulate the PAR synthesis/degradation ratio at the transcription level. The accumulation of NAD+ molecules in cells might be transiently caused by mitochondrial dysfunction, which is usually accompanied by insufficient OXPHOS or aberrant respiration [87, 88]. However, when DNA damage eventually activates PARP, NAD+ molecules will be consumed to synthesize PAR polymer in the nuclei or mitochondria. Thus, the decrease in the NAD+/NADH ratio would not only reduce the activities but also the expression of enzymes that function in the NAD+-dependent TCA cycle progression. At this point, cells will have to produce ATP in a mitochondria-independent manner. This metabolic change would be observed as the “Warburg effect” in cancer cells [5, 6].

3.2. The regulation of TFs and nucleotide binding proteins by poly(ADP-ribosyl)ation

PARP inhibitors, such as talazoparib, niraparib, rucaparib, olaparib, and veliparib, are clinically used for the treatment of cancer, especially when BRCA1 and BRCA2 gene mutations are present [89]. They all interact with the NAD+-binding site of the catalytic domain of PARP1 and PARP2. A recent study indicated that the NAD+-binding pocket of the PARP1 regulates interaction with DBC1, which is deleted in breast cancer 1, which is a known SIRT1 inhibitor protein [90]. A decrease in the NAD+ will upregulate the interaction between DBC1 and PARP1, leading to the suppression of its activity. This might partly explain why DNA repair declines with aging [91]. The poly(ADP-ribosyl)ation of proteins not only initiates the response to DNA damage, but also regulates the transcription of specific genes [92]. The poly(ADP-ribosyl)ation of C/EBPβ by PARP-1 modulates its transcriptional activity to enhance the expression of the genes encoding factors that regulate adipogenesis [93]. A recent study showed that the poly(ADP-ribosyl)ation of an RNA-binding protein HuR by PARP1 stabilizes Cxcl2 gene transcripts [94]. Moreover, the poly(ADP-ribosyl)ation of FoxO3 suppresses its transcriptional activity and leads to cardiac hypertrophy [95]. Taken together, poly(ADP-ribosyl)ation, which consumes NAD+ as a substrate for PAR synthesis, may regulate transcription to respond to DNA damage-induced signals. Thus, it should be noted that PARP inhibitors not only limit the DNA damage response to lead to the death of cancerous cells, but also reduce the consumption of NAD+ molecules to modulate the transcription of specific genes.


4. Epigenetic alterations in chromosomal DNAs and proteins

Epigenetic alterations are frequently found in cancer, implying that “cancer is an epigenetic disease” [96]. It has been hypothesized that epigenetic and/or transcriptional changes play a role in determining the chromatin state in tumor cells [97]. Epigenetic regulation is mainly driven by modifications of chromosomal DNAs and histone proteins [98]. The biological relevance between cellular metabolites and the gene expression has been proposed as the RNA/enzyme/metabolite (REM) networking system [99]. The metabolites, NAD+, S-adenosylmethionine (AdoMet), and acetyl-CoA, are the substrates for poly (ADP-ribosyl)ation, methylation, and acetylation, respectively [76], suggesting that these metabolic state-dependent molecules play important roles in the epigenetic regulation.

4.1. The possible functions of poly(ADP-ribosyl)ation on epigenetic regulation

NAD+ not only plays important roles in DNA repair, mitochondrial functions, and cellular senescence [72, 100], but also affects the modification of chromatin proteins [77] and modulates the gene expression regulatory system [101]. More importantly, NAD+ is a substrate for the PARP enzyme to synthesize PAR macromolecules, which modify both PARP itself and chromosomal proteins and DNA repair factors [67]. Histones and HMGB (High mobility group box) proteins can be poly(ADP-ribosyl)ated [102, 103, 104, 105], suggesting that modifications by such macromolecules on chromosomes affect the epigenetic regulation of the gene expression system. Moreover, poly(ADP-ribosyl)ation on the chromosomal insulator protein CTCF (CCCTC-binding factor) may be involved in epigenetic regulation [106, 107]. Recently, it was shown that CTCF binds directly to PAR to be recruited at DNA lesion sites, indicating that the CTCF also plays a role in the DNA damage response [108]. It has been suggested that poly(ADP-ribosyl)ation affects the methylation patterns in chromosomal DNAs [109, 110]. A recent study showed that the transcriptional regulation of the EZH2 gene, which encodes the catalytic subunit of the polycomb repressive complex 2 (PRC2), by PARP1 [111], affects the methylation of chromatin proteins [112]. Because the incidence of cancer increases with aging [113], a decline in the cellular level of NAD+, which might accompany the decrease in PARP activity [114]. SIRT1, which depends on the NAD+ molecule to de-acetylate histone proteins, plays important roles in the aging process [115]. Taken together, these observations imply that NAD+ and its polymerized form, PAR, are involved in epigenetic regulation, and that it may be altered in line with the aging process.

4.2. The DNA methylation of chromosomal DNAs

The methylation of promoter regions of specific genes in human chromosomes can be used as biomarkers in various cancers [116]. The DNA methylation reaction is catalyzed by methyltransferases (DNMTs), which utilize AdoMet as a methyl group donor [117]. A recent study showed that intragenic DNA methylation, which is carried out by Dnmt3b in mouse embryonic stem cells, protects the gene body from the entry of spurious RNA pol II and the initiation of cryptic transcription [118]. The extended data showed that the ETS factor binding regions are sensitive to the knock out of the Dnmt3b gene, suggesting that the occupation of the GGAA (TTCC)-motifs by GGAA-motif binding proteins could be epigenetically controlled by methylation. Furthermore, the regulation of demethylation by ten-eleven translocation (TET)-family enzymes [119], the activity of which is reduced by hypoxia, should not be ignored. Hypoxia-induced hyper methylation has been demonstrated to occur on the promoter regions of the DNA repair factor-encoding genes, including BRCA1, FANCD2, FANCF, POLL, and UNG [120]. Of note, the duplicated GGAA-motifs are contained in these gene promoters [53]. A methylation sensitive SELEX analysis showed that ETS-binding was inhibited by mCpG, though NFAT, which also recognizes the GGAA-core motif sequence and preferentially binds to methylated DNA [121]. The observation suggests that GGAA-motif recognizing TFs could be classified into two groups according to their preference to DNA methylation.

The SET protein is an epigenetic regulatory factor that promotes loss of methylation through direct interaction with hypo-acetylated histones [122]. A genome-wide analysis showed that DNA hypermethylation is apparently induced in old male adults, relative to young male adults, suggesting a relationship between DNA methylation and aging [123, 124, 125]. Moreover, the methylation and demethylation of the lysine residues of histones might affect the regulation of transcription [126]. In summary, AdoMet, a methyl group donor, plays an important role in epigenetic control.

4.3. The acetylation of histones could regulate the generation or progression of cancers

Acetyl-CoA is required for acetylation on the lysine residue of histones [127]. This process is catalyzed by acetyltransferases (HATs), including KAT2A (GCN5), KAT2B (CAF), KAT5 (ESA1), KAT7 (HBO1), and KAT8 (MOF) [128], which can be classified into two major groups: the GCNT and MYST families [129]. At least 11 enzymes are known to be histone deacetylases (HDACs) [130]. Because the increased or aberrant expression of HDACs has been reported in various cancers, inhibitors or modulators of HDACs are expected to be effective as anticancer drugs [131]. On the other hand, the lysine acetylation is negatively regulated by sirtuin proteins, including SIRT1 [116], which de-acetylate proteins, utilizing NAD+ as an acceptor of the acetyl group [127]. It is hypothesized that a reduction in nutrient levels could induce the accumulation of NAD+ to activate sirtuins. Histone de-acetylation is consistent with the finding that CR mimetics prolong the life span [131, 132, 133]. In cancer cells, if mitochondrial dysfunction occurs with a reduction in the NAD+ level or the hindrance of the progression of the TCA cycle, acetyl-CoA might only be converted to citrate to be used as an acetyl group donor for histones in the nuclei. If so, an increase in histone acetylation would occur naturally in the course of oncogenesis. The activation of HDACs in cancer cells might be the response to the aberrant hyper-acetylation of histone proteins that could lead to the abnormal transcription of various genes, including the mitochondrial function-associated genes.

To summarize, key metabolites, NAD+ and acetyl-CoA could regulate DNA methylation and histone acetylation directly or indirectly, and play essential roles in epigenetic control.


5. Mitonuclear communication regulates apoptosis, DNA repair, and  aging

The mechanisms by which nuclear DNA damage signaling causes the mitochondrial dysfunctions that accelerate aging and aging-related diseases including cancer have been investigated in a review [134]. This process can be referred to as “mitonuclear communication” [135], suggesting that DNA repair systems are integrated into the mitochondrial functions. Given that α proteobacteria are the putative ancestors of the mitochondria [136], they need to take care of the nuclear DNAs that contain almost all (99%) of their essential protein-encoding genes [9]. Thus, the mitochondria might have developed a nuclear genome monitoring system, especially when DNA damage is induced. Several TCA cycles or metabolic enzymes functions as tumor suppressors [59, 64, 137], suggesting that mitochondrial dysfunction may lead to cancerous states.

5.1. The mitochondria play the role of judge in the decision to induce cell death

The execution of apoptosis is mediated by the mitochondria in response to various stresses, including DNA damage and immunological stress signals [138, 139, 140]. Thus, the mitochondria are known to serve as master regulators of danger signaling to determine cell death or survival [141]. Several mechanisms, including the regulation of the regulators of apoptosis [142, 143] and miRNAs [144], are involved in the induction of apoptosis. The surveillance of the human genomic DNA database indicated the presence of the duplicated GGAA-motifs in the 5′-regulatory regions of the human PDCD1, DFFA, BCL2, FAS, FASL, ATG12/AP3S1, APOPT1/BAG5, and HTRA2/AUP1 genes [13, 53, 54]. These observations suggest that the expression of the apoptosis regulating factor-encoding genes is modulated by the GGAA-duplicated sequences. In this context, apoptosis or programmed cell death, which is controlled by the mitochondria, partly depends on the GGAA-motif binding TFs.

5.2. The localization of p53 and other DNA repair factors in the mitochondria and the regulation of their gene expression

Recent studies have shown that the p53 protein not only acts as a “guardian of the genome”, but also serves as a regulator of metabolism [145, 146]. Moreover, p53 has been reported to accumulate in the mitochondria in response to stress [147]. Besides p53, a number of widely known DNA repair factors, including ATM, BRCA1, PARP, PARG, and RB, localize in the mitochondria or regulate their functions [148, 149, 150, 151, 152]. The surveillance of the 5′-upstream regions of these DNA repair factor-encoding genes revealed that they commonly possess duplicated GGAA-motifs [53, 78].

GGAA-motif duplications are found in the bidirectional APEX1/OSGEP promoter region. The APEX1 encodes apurinic/apyrimidinic endonuclease 1 (APE1) that regulates both the base excision repair (BER) and the mitochondrial DNA repair systems [75, 153]. The GGAA-duplication is contained in the regulatory region of the head–head configured ACO2/PHF5A genes [54]. The ACO2 gene encodes aconitase, which plays an important role in the TCA cycle to produce citrate and isocitrate, and which also serves as a mitochondrial redox-sensor [154]. Importantly, aconitase and mitochondrial BER enzyme OGG1 (8-oxoguanine DNA glycosylase) cooperatively preserve mitochondrial DNA integrity [155]. We also confirmed that the duplicated GGAA-motifs were present in the 5′-upstream regions of the genes associated with Fanconi’s anemia (FA) [53], which encode the DNA repair factors that are shown to regulate nucleotide excision repair and genome stability [156]. Interestingly, it was shown that mitochondrial dysfunction forces FA cells to produce energy by glycolysis [157], suggesting that FA proteins might be involved in the metabolic switch system in cancer cells. Additionally, Cockayne syndrome proteins CSA and CSB, which play roles in nucleotide excision repair (NER), accumulate in the mitochondria under oxidative stress [158]. In KRAS/LKB1-mutant lung cancer cells, carbamoyl phosphate synthetase-1 (CPS1), which is localized in mitochondria and which eliminates NH4 to initiate the urea cycle, also plays a role in controlling the pyrimidine/purine balance to regulate the integrity of nuclear DNAs [159]. In this circumstance, the silencing of the CPS1 gene expression leads to an incomplete S-phase or apoptotic cell death due to increased DNA damage. As expected, the duplicated GGAA is present in the CPS1/LANCL1 bidirectional promoter region. However, no such element is found near the TSSs of either the CAD or ASS1 genes, which encode cytoplasmic enzymes carbamoyl phosphate syntetase-2 and argininosuccinate synthase, respectively. These observations suggest that expression of the mitochondria-localizing, DNA repair-associated protein-encoding genes could be cooperatively regulated by duplicated GGAA-motif binding TFs, supporting the hypothesis that mitochondrial dysfunction causes oncogenesis [8].

5.3. The communication between telomeres and mitochondria may depend on the NAD+/ NADH ratio

The telomeres and mitochondria are thought to communicate with each other [160]. Several nuclear DNA repair factors play roles in the maintenance of mtDNAs, and damaged mtDNAs in turn exert signals to regulate nuclear transcription [74]. The system by which DNA repair/energy production is monitored might be mediated by the balance of the NAD+/NADH ratio, which is regulated by a number of enzymes in the nuclei, mitochondria, and cytosol [161]. In breast cancer cells, the crosstalk between BRCA1 and PARP1 maintains the stability of the DNA repair ability, which would be partly sensitive to the NAD+ concentration [162].

The mitochondria might have conveniently deposited their function-associated genes into the nuclei, but need to take care, especially when DNA damage occurs. However, high-dose or repeated DNA damage may eventually activate the PARP enzyme, which consumes NAD+ as a substrate for the synthesis of PAR, to initiate the DNA repair system [66]. The decrease in the NAD+ level will subsequently cause incomplete TCA cycle progression and the dysregulation of respiration/OXPHOS, accompanied by the reduced expression of the mitochondrial function-associated genes. At this stage, the “Warburg effect” can be observed (Figure 1).

Figure 1.

Toward the establishment of a novel cancer therapy. Cellular NAD+ molecules will decrease in accordance with aging or increased levels of various types of stress, especially DNA damage, which activates the PARP enzyme, which synthesizes PAR to consume NAD+ as a substrate. Subsequently, alterations in the transcriptional profile might occur, leading to a reduction or the mismanagement of the mitochondrial functions. In these circumstances, energy producing mitochondrial respiratory systems will decline or be dysregulated, while glycolysis will be enhanced providing ATP molecules that allow cells to proliferate in an unrestricted manner. Novel cancer therapies should be based on the concept that they will never kill cancer cells; rather, they should force the cells to regain their normal respiratory systems, including the TCA cycle and OXPHOS. The recovery of these mitochondria might also lead to the restoration of the mitonuclear communication system. In order to establish a gene therapy, it is necessary to reveal the molecular mechanisms that control the transcription of the mitochondrial function-associated genes.


6. The involvement of nicotinamide adenine dinucleotide (NAD+) in oncogenesis and the aging process

The biological relevance of the NAD+ molecule, especially in relation to its pivotal roles in metabolism and the protection of chromosomal DNAs, has been discussed in detail [66, 67]. A recent study showed that nuclear PAR can be utilized by NUDIX5 to supply ATP molecules, which are required for chromatin remodeling [86]. Moreover, NAD+ and its precursor nicotinamide have been reported to ameliorate metabolism or the mitochondrial functions [163, 164, 165].The repletion of NAD+ improves the mitochondrial functions to prolong the life span of adult mouse stem cells [166]. Conversely, decreased concentrations of NAD+ could cause aging or aging-related diseases [75]. These observations suggest that the NAD+ level may be correlated with mitohormesis [167], and that nutrient sensing molecules may control aging [57].

6.1. NAD+ restricts the generation and development of cancer by supporting the mitochondrial functions

Several drugs that induce an increase in the intracellular NAD+ level are expected to contribute to the establishment of novel therapeutics for treating age-related diseases, including cancer [168]. Mitochondrial dysfunction has been suggested to be associated with the development of tumors or cancerous cells [169, 170]. In breast cancer cells, the knockdown of the subunit NDUFV1 leads to an aberration in complex I, which was shown to enhance aggressiveness or metastasis [171]. An increase in the cellular level of NAD+ may be associated with the improvement of the mitochondrial integrity to suppress oncogenesis. PGC-1α, which upregulates mitochondrial biogenesis, drives NAD+ biosynthesis and thereby induces stress resistance [172]. A recent study showed that PGC-1α suppresses the metastasis of melanoma, acting on the transcription program, namely the PGC-1α-ID2-TCF-integrin axis [173].

A loss of CSB, which can localize in the mitochondria [158], activates PARP1 to synthesize PAR [174], suggesting that the dysregulation of the mitochondrial functions to regulate DNA repair system may reduce the NAD+/NADH molecular ratio.

6.2. NAD+-dependent transcription of DNA repair factor-encoding genes

It is worth noting again that the NAD+ molecule is the substrate for the PARP enzyme, which is required for the DNA damage response and the DNA repair system [66, 67]. The inhibition of the PARP1 enzyme ameliorates the mitochondrial metabolism through the activation of SIRT1 [175]. Conversely, the over-activation of the PARP1 enzyme can lead to mitochondrial dysfunction [176]. The PARP1 gene expression was found to be negatively regulated when poly(ADP-ribose) glycohydrolase (PARG) siRNAs were introduced into HeLa S3 cells [40], suggesting that the degradation of the PAR macromolecule is required for the transcription of the PARP1 gene. Because the 5′-upstream regions of both the human PARP1 and PARG genes commonly contain the duplicated GGAA-motifs [53, 54], these two genes may be regulated by an NAD+-sensitive mechanism. The results support the concept that PARP1 is involved in the NAD+-sensitive transcription system [85]. In summary, the NAD+/NADH ratio not only contributes to the DNA repair, but also to the fine-tuning of the transcription of genes that encode the NAD+ metabolism-associated DNA repair factors.

As described previously, the promoter regions of a number of genes that encode TCA cycle enzymes and DNA repair factors contain duplicated GGAA (TTCC) motifs [53, 54]. Thus, the fine-tuning of the transcription of mitochondrial function-associated factor- and DNA repair factor-encoding genes would be required for cells to conduct mitochondria in response to DNA damage-inducing stress.


7. The development of novel cancer therapeutics to improve mitochondrial functions

In cancer cells, the mitochondrial functions are downregulated but glycolysis is upregulated [7, 8]. Thus, inhibitors of glycolysis/PDHK1/PARP, which target the metabolic switch in cancer cells, could be effective anti-cancer drugs [59]. In general, glycolysis- or glycolytic pathway-targeting drugs are expected to kill cancer cells specifically. For example, 2-deoxy-d-glucose, cisplatin and 5-FU—which have an inhibitory effect on glycolysis—are used to treat cancer in the clinical setting [177]. However, glycolysis is one of the most essential biological reactions. Thus, glycolysis inhibitors may be harmful or toxic to normal cells. Given that mitochondrial dysfunction is another essential cause of oncogenesis, the improvement of the mitochondria might provide clues that can be used to design innovative next-generation cancer therapies.

7.1. Chemicals that will initiate the recovery of mitochondria

Our previous in vitro studies showed that Rsv moderately upregulates the expression of various duplicated GGAA-motif-driven genes, including TP53 and HELB [46, 48, 78]. Given that the increase in the NAD+/NADH ratio can improve the mitochondrial functions, the introduction of the redox reaction-associated genes may be applied in cancer treatment. PARP inhibitors, which are especially effective for treating cancer with BRCA1 and BRCA2 mutations by disrupting specific types of DNA repair systems, are clinically approved drugs [89]. Another compound is TEMPOL, an antioxidant that has a suppressive effect on tumor cell proliferation [178], which increases the cellular NAD+ level, supporting the DNA repair system [179, 180]. A number of compounds that target mitochondria have been tested in clinical trials [181]. Tocotrienols and their analogues target mitochondria and the immune system, causing the death of cancer cells [182]. Metformin and rapamycin are also expected to be novel anti-cancer/aging drugs that effectively suppress mTOR signaling [183]. Activators of mTOR, AMPK, and PGC-1α have been shown to have a synergistic effect with PD-1 blockade therapy [184], suggesting that mitochondrial activation can augment the immune response.

7.2. Possible gene-therapies that improve the mitochondrial functions

PGC-1α, which is encoded by the PPARGC1A gene, has been shown to be involved in the de novo synthesis of the NAD+ [172]. Recently, it was reported that lactamase β (LACTB) is a multifunctional protein, which suppresses tumors through its effects on the mitochondrial lipid metabolism [185]. LACTB is included in mitochondrial complex I and treatment of fibroblast cells with its siRNA reduces complex I activity [186]. It therefore works as an upregulator of NAD+. As expected, multiple duplications of the GGAA-motif are present in the bidirectional promoter region between the LACTB (MRPL56) gene and the bidirectional partner LOC107987798. We confirmed that the duplicated GGAA-motif is present near the TSS of the human PDSS2 gene, which encodes prenyl-diphosphatase synthase subunit 2, which is a modulator of the complex I–III and II–III [133]. The PDSS2 is required for the integrity of Coenzyme Q (CoQ) or ubiquinone, which can improve the mitochondrial functions [187]. Thus, PDSS2 would be one of the targets for novel anticancer agents [188, 189]. The introduction of the LbNOX gene, which encodes bacterial NADH oxidase, into HeLa cells via a lentiviral vector ameliorates the proliferative and metabolic defects caused by the impairment of the electron transport chain (ETC) [190].These lines of evidence suggest that NAD+ metabolism regulator encoding genes, including PARP, PARG, and NAMPT, as well as the PPARGC1A, LACTB, PDSS2, and LbNOX genes, could be applied or targeted in anti-cancer gene therapy.

Alternatively, TF-encoding genes can be applied to anti-cancer therapies that aid in the recovery of mitochondria. First, the transcription modulator CtBP might be artificially controlled to suppress oncogenesis or cancer progression [83, 84]. Second, because duplicated GGAA-motifs are present in the 5′-upstream regions of a number of DNA repair factor- and mitochondrial factor-encoding genes, GGAA-motif binding factors could upregulate the mitochondrial functions at the transcriptional level. Recently, it was reported that mouse Gabp, which is an ETS family protein, is required for mitochondrial biogenesis through the regulation of the Tfb1m gene [191], suggesting that a GABP expression vector might be designed and constructed for cancer treatment. The 5′-upstream regions of a number of human genes contain the GGAA-duplication, and it is a GC-box that is very frequently found near the GGAA-core motif [12]. Recently, it was reported that mutations on the ETS family protein-encoding ERF and ERG genes play roles in prostate oncogenesis [192], implying that imbalances in GGAA-binding TFs could lead to aberrant gene expression. In order to determine which TF-encoding genes should be chosen, the mechanisms through which each of these genes is differently regulated during tumorigenesis should be elucidated.


8. Conclusions and future prospects

In this article, we focused on the transcription mechanism that regulates the mitochondrial functions and the DNA repair systems, both of which decline with aging. Although the molecular mechanisms underlying the regulation of the expression of these genes are not yet fully understood, several lines of evidence suggest that it is dependent on the NAD+/NADH balance.

The anti-cancer drugs that are currently in use, including metabolism inhibitors, telomerase inhibitors, and apoptosis inducers, were developed with the common intention of killing cancer cells. Although immune receptor target drugs have been applied in the clinical setting, they are similar in that they force cancer cells to die. The anti-cancer drugs that are currently in use damage both malignant cancer cells and normal healthy cells. Importantly, the undesired effects of these anti-cancer drugs are problematic with regard to the quality of life (QOL) of cancer patients, especially those who are too old to endure severe adverse effects that occur during the course of chemotherapy. In order to avoid lethal side effects, individual whole genome sequencing to identify drug sensitivities, the development of a side-effect monitoring system, and the improvement of treatment policies could be adapted. These are the burdens that are necessitated by the intrinsic concept underlying the development and creation of most anti-cancer drugs.

In the near future, novel anti-cancer drugs or therapies must be developed and established. These drugs should not kill cancer cells; rather they should give them a chance to regain the right mitochondrial functions and DNA repair systems, and immunological responses. Natural or chemical compounds can ameliorate the NAD+/NADH level to improve the mitochondrial functions, DNA repair systems, and even immune responses. Alternatively, specific TF expression vector(s) could be introduced into cancer cells to lead them to recover to a healthy state. A number of promoter regions of the mitochondrial function-, DNA repair-, and anti-viral/tumor factor-encoding genes have duplicated GGAA-motifs with GC-boxes. Needless to say, it is necessary to determine the TFs that should and should not be applied prior to their clinical use. Based on this novel concept, the design of anticancer/tumor drugs or gene transfer vector(s) will contribute to the prevention of aging and its associated diseases, including cancer.



The authors are grateful to Asuka Shinozaki, Akiko Kawahara, Erisa Murayama, and Mayu Yamamura for their discussion and outstanding technical assistance.



CRcaloric restriction
FAFanconi’s anemia
HDAChistone deacetylase
ISGinterferon-stimulated gene
OXPHOSoxidative phosphorylation
PARGpoly(ADP-ribose) glycohydrolase
PARPpoly(ADP-ribose) polymerase
TFtranscription factor
TSStranscription start site


  1. 1. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502(7471):333-339
  2. 2. Rahman N. Realizing the promise of cancer predisposition genes. Nature. 2014;505(7483):302-308
  3. 3. Aronson S, Rehm H. Building the foundation for genomics in precision medicine. Nature. 2015;526(7573):336-342
  4. 4. Wishart DS, Mandal R, Stanislaus A, Ramirez-Gaona M. Cancer metabolomics and the human metabolome database. Metabolomics. 2016;6(1):E10
  5. 5. Warburg O. On the origin of cancer cells. Science. 1956;123(3191):309-314
  6. 6. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science. 2009;324(5930):1029-1033
  7. 7. Seyfried TN, Flores RE, Poff AM, D’Agostino DP. Cancer as a metabolic disease: Implications for novel therapeutics. Carcinogenesis. 2014;35(3):515-527
  8. 8. Seyfried TN. Cancer as a mitochondrial metabolic disease. Frontiers in Cell and Developmental Biology. 2015;3:43
  9. 9. Vafai SB, Mootha VK. Mitochondrial disorders as windows into an ancient organelle. Nature. 2012;491(7424):374-383
  10. 10. Oikawa T, Yamada T. Molecular biology of the Ets family of transcription factors. Gene. 2003;303:11-34
  11. 11. Hsu T, Trojanowska M, Watson DK. Ets proteins in biological control and cancer. Journal of Cellular Biochemistry. 2004;91(5):896-903
  12. 12. Hollenhorst PC, Shah AA, Hopkins C, Graves BJ. Genome-wide analyses reveal properties of redundant and specific promoter occupancy within the ETS gene family. Genes & Development. 2007;21(15):1882-1894
  13. 13. Uchiumi F, Miyazaki S, Tanuma S. The possible functions of duplicated ets (GGAA) motifs located near transcription start sites of various human genes. Cellular and Molecular Life Sciences. 2011;68(12):2039-2051
  14. 14. Uchiumi F, Miyazaki S, Tanuma S. Biological functions of the duplicated GGAA-motifs in various human promoter regions. Yakugaku Zasshi. 2011;1311(12):1787-1800
  15. 15. Kerr IM, Stark GR. The control of interferon-inducible gene expression. FEBS Letters. 1991;285(2):194-198
  16. 16. Sheikh SZ, Kobayashi T, Matsuoka K, Onyiah JC, Plevy SE. Characterization of an interferon-stimulated response element (ISRE) in the Il23a promoter. The Journal of Biological Chemistry. 2011;286(2):1174-1180
  17. 17. Chen YQ, Sengchanthalangsy LL, Hackett A, Ghosh G. NF-kappaB p65 (RelA) homodimer uses distinct mechanisms to recognize DNA targets. Structure. 2000;8(4):419-428
  18. 18. Nelson N, Marks MS, Driggers PH, Ozato K. Interferon consensus sequence-binding protein, a member of the interferon regulatory factor family, suppresses interferon-induced gene transcription. Molecular and Cellular Biology. 1993;13(1):588-599
  19. 19. Wang IM, Contursi C, Masumi A, Ma X, Trinchieri G, Ozato K. An IFN-γ-inducible transcription factor, IFN consensus sequence binding protein (ICSBP), stimulates IL12 p40 expression in macrophages. Journal of Immunology. 2000;165(1):271-279
  20. 20. Nguyen VT, Benveniste EN. Involvement of STAT-1 and Ets family members in interferon-γ induction of CD40 transcription in microglia/macrophages. The Journal of Biological Chemistry. 2000;275(31):23674-23684
  21. 21. Aittomäki S, Yang J, Scott EW, Simon MC, Silvennoinen O. Molecular basis of Stat1 and PU.1 cooperation in cytokine-induced Fcg receptor 1 promoter activation. International Immunology. 2004;16(2):265-274
  22. 22. Kumar P, Garg R, Bolden G, Pandey KN. Interactive roles of Ets-1, Sp1, and acetylated histones in the retinoic acid-dependent activation of guanylyl cyclase/atrial natriuretic peptide receptor-A gene transcription. The Journal of Biological Chemistry. 2010;285(48):37521-37530
  23. 23. FitzGerald PC, Shlyakhtenko A, Mir AA, Vinson C. Clustering of DNA sequences in human promoters. Genome Research. 2004;14(8):1562-1574
  24. 24. Jin E, Liu J, Suehiro J, Yuan L, Okada Y, Nikolova-Krstevski V, et al. Differential roles for ETS, CREB, and EGR binding sites in mediating VEGF receptor 1 expression in vivo. Blood. 2009;114(27):5557-5566
  25. 25. Chen HG, Han WJ, Deng M, Qin J, Yuan D, Liu JP, et al. Transcriptional regulation of PP2A-A alpha is mediated by multiple factors including AP-2alpha, CREB, ETS-1, and SP-1. PLoS One. 2009;4(9):e7019
  26. 26. Perry DJ, Austin KJ, Hansen TR. Cloning of interferon-stimulated gene 17: The promoter and nuclear proteins that regulate transcription. Molecular Endocrinology. 1999;13(7):1197-1206
  27. 27. Rouyez MC, Lestingi M, Charon M, Fichelson S, Buzyn A, Dusanter-Fourt I. IFN regulatory factor-2 cooperates with STAT1 to regulate transporter associated with antigen processing-1 promoter activity. Journal of Immunology. 2005;174(7):3948-3958
  28. 28. Masumi A, Hamaguchi I, Kuramitsu M, Mizukami T, Takizawa K, Momose H, et al. Interferon regulatory factor-2 induces megakaryopoiesis in mouse bone marrow hematopoietic cells. FEBS Letters. 2009;583(21):3493-3500
  29. 29. Cho HY, Lee SW, Seo SK, Choi IW, Choi I, Lee SW. Interferon-sensitive response element (ISRE) is mainly responsible for IFN-α-induced upregulation of programmed death-1 (PD-1) in macrophages. Biochimica et Biophysica Acta. 2008;1779(12):811-819
  30. 30. De Veer MJ, Holko M, Frevel M, Walker E, Der S, Paranjape JM, et al. Functional classification of interferon-stimulated genes identified using microarrays. Journal of Leukocyte Biology. 2001;69(6):912-920
  31. 31. Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, et al. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature. 2011;472(7344):481-485
  32. 32. Uchiumi F, Larsen S, Masumi A, Tanuma S. The putative implications of duplicated GGAA-motifs located in the human interferon regulated genes (ISGs). In: Genomics I-Humans, Animals and Plants. Hong Kong: iConcept Press Ltd; 2013. p. 87-105
  33. 33. Larsen S, Kawamoto S, Tanuma S, Uchiumi F. The hematopoietic regulator, ELF-1, enhances the transcriptional response to Interferon-β of the OAS1 anti-viral gene. Scientific Reports. 2015;5:17497
  34. 34. Sementchenko VI, Watson DK. Ets target genes: Past, present and future. Oncogene. 2000;19(55):6533-6548
  35. 35. Takaoka A, Hayakawa S, Yanai H, Stoiber D, Negishi H, Kikuchi H, et al. Integration of interferon-α/β signaling to p53 responses in tumor suppression and antiviral defense. Nature. 2003;424(6948):516-523
  36. 36. Lee SH, Kim JW, Lee HW, Cho YS, Oh SH, Kim YJ, et al. Interferon regulatory factor-1 (IRF-1) is a mediator for interferon-gamma induced attenuation of telomerase activity and human telomerase reverse transcriptase (hTERT) expression. Oncogene. 2003;22(3):381-391
  37. 37. Barnes BJ, Kellum MJ, Pinder KE, Frisancho JA, Pitha PM. Interferon regulatory factor 5, a novel mediator of cell cycle arrest and cell death. Cancer Research. 2003;63(19):6424-6431
  38. 38. Xiong GM, Gasser S. Integration of the DNA damage response with innate immune pathways. In: Vengrova S, editor. DNA Repair and Human Health. InTech OPEN: Rijeka, Croatia; 2011. p. 715-742
  39. 39. Yokoyama Y, Kawamoto T, Mitsuuchi Y, Kurosaki T, Toda K, Ushiro H, et al. Human poly(ADP-ribose) polymerase gene. Cloning of the promoter region. European Journal of Biochemistry. 1990;194(2):521-526
  40. 40. Uchiumi F, Watanabe T, Ohta R, Abe H, Tanuma S. PARP1 gene expression is downregulated by knockdown of PARG gene. Oncology Reports. 2013;29(5):1683-1688
  41. 41. Wei L, Nakajima S, Hsieh CL, Kanno S, Masutani M, Levine AS, et al. Damage response of XRCC1 at sites of DNA single strand breaks is regulated by phosphorylation and ubiquitylation after degradation of poly(ADPribose). Journal of Cell Science. 2013;126(Pt 19):4414-4423
  42. 42. Niere M, Mashimo M, Agledal L, Dölle C, Kasamatsu A, Kato J, et al. ADP-ribosylhydrolase 3(ARH3), not poly(ADP-ribose) glycohydrolase (PARG) isoforms, is responsible for degradation of mitochondrial matrix associated poly(ADP-ribose). The Journal of Biological Chemistry. 2012;287(20):16088-16102
  43. 43. Leung A, Todorova T, Ando Y, Chang P. Poly(ADP-ribose) regulate post-transcriptional gene regulation in the cytoplasm. RNA Biology. 2012;9(5):542-548
  44. 44. Gibson BA, Kraus WL. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nature Reviews. Molecular Cell Biology. 2012;13(7):411-424
  45. 45. Zhou B, Ikejima T, Watanabe T, Iwakoshi K, Idei Y, Tanuma S, et al. The effect of 2-deoxy-D-glucose on Werner syndrome RecQ helicase gene. FEBS Letters. 2009;583(8):1331-1336
  46. 46. Uchiumi F, Watanabe T, Hasegawa S, Hoshi T, Higami Y, Tanuma S. The effect of Resveratrol on the Werner Syndrome RecQ helicase gene and telomerase activity. Current Aging Science. 2011;4(1):1-7
  47. 47. Ingram DK, Zhu M, Mamczarz J, Zou S, Lane MA, Roth GS, et al. Calorie restriction mimetics: An emerging research field. Aging Cell. 2006;5(2):97-108
  48. 48. Uchiumi F, Arakawa J, Iwakoshi K, Ishibashi S, Tanuma S. Characterization of the 5′-flanking region of the human DNA helicase B (HELB) gene and its response to trans-resveratrol. Scientific Reports. 2016;6:24510
  49. 49. Taneja P, Gu J, Peng R, Carrick R, Uchiumi F, Ott RD, et al. A dominant-negative mutant of human DNA helicase B blocks the onset of chromosomal DNA replication. The Journal of Biological Chemistry. 2002;277(43):40853-40861
  50. 50. Gu J, Xia X, Yan P, Liu H, Podust VN, Reynolds AB, et al. Cell cycle-dependent regulation of a human DNA helicase that localizes in DNA damage foci. Molecular Biology of the Cell. 2004;15(7):3320-3332
  51. 51. Guler GD, Liu H, Vaithiyalingam S, Arnett DR, Kremmer E, Chazin WJ, et al. Human DNA helicase B (HDHB) binds to replication protein A and facilitates cellular recovery from replication stress. The Journal of Biological Chemistry. 2012;287(9):6469-6481
  52. 52. Tkáč J, Xu G, Adhikary H, Young JT, Gallo D, Escribano-Díaz C, et al. HELB is a feedback inhibitor of DNA end resection. Molecular Cell. 2016;61(3):405-418
  53. 53. Uchiumi F, Larsen S, Tanuma S. Transcriptional regulation of the human genes that encode DNA repair- and mitochondrial function-associated proteins. In: Chen C, editor. Advances in DNA Repair. Rijeka, Croatia: InTech OPEN; 2015. p. 129-167
  54. 54. Uchiumi F, Fujikawa M, Miyazaki S, Tanuma S. Implication of bidirectional promoters containing duplicated GGAA motifs of mitochondrial function-associated genes. AIMS Molecular Science. 2013;1(1):1-26
  55. 55. Seyfried TN, Shelton LM. Cancer as a metabolic disease. Nutrition and Metabolism. 2010;7:7
  56. 56. Schultze A, Harris AL. How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature. 2012;491(7424):364-373
  57. 57. López-Otín C, Serrano M, Partridge L, Blasco MA, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194-1217
  58. 58. Gomes AP, Price NL, Ling AJY, Mosiehi JJ, Montgomery MK, Rajman L, et al. Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013;155(7):1624-1638
  59. 59. Pollard PJ, Brière JJ, Alam NA, Barwell J, Barclay E, Wortham NC, et al. Accumulation of Krebs cycle intermediates and over-expression of HIFalpha in tumors which result from germline FH and SDH mutations. Human Molecular Genetics. 2005;14(15):2231-2239
  60. 60. Hoekstra AS, de Graaff MA, Briaire-de Bruijn IH, Ras C, Seifar RM, van Minderhout I, et al. Inactivation of SDH and FH cause loss of 5hmC and increased H3K9me3 in paraganglioma/pheochromocytoma and smooth muscle tumors. Oncotarget. 2015;6(36):38777-38788
  61. 61. Desideri E, Vegliante R, Ciriolo MR. Mitochondrial dysfunctions in cancer: Genetic defects and oncogenic signaling impinging on TCA cycle activity. Cancer Letters. 2015;356(2 Pt A):217-223
  62. 62. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739-744
  63. 63. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al. IDH1 and IDH2 mutations in gliomas. The New England Journal of Medicine. 2009;360(8):765-773
  64. 64. Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, et al. IDH mutation impairs histonedemethylation and results in a block to cell differentiation. Nature. 2012;483(7390):474-478
  65. 65. Tan B, Young DA, Lu Z-H, Meier TI, Shepard RL, Roth K, et al. Pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), an enzyme essential for NAD+ biosynthesis, in human cancer cells. The Journal of Biological Chemistry. 2012;288(5):3500-3511
  66. 66. Maruta H, Okita N, Takasawa R, Uchiumi F, Hatano T, Tanuma S. The Involvement of ATP produced via (ADP-Ribose)(n) in the maintenance of DNA replication apparatus during DNA Repair. Biological & Pharmaceutical Bulletin. 2007;30(3):447-450
  67. 67. Tanuma S, Sato A, Oyama T, Yoshimori Y, Abe H, Uchiumi F. New insights into the roles of NAD+-poly(ADP-ribose) metabolism and poly(ADP-ribose) glycohydrolase. Current Protein & Peptide Science. 2016;17(7):668-682
  68. 68. Uchiumi F, Larsen S, Tanuma S. Possible roles of a duplicated GGAA motif as a driver cis-element for cancer-associated genes. In: Understand Cancer – Research and Treatment. Hong Kong, iConcept Press Ltd; 2016. p. 1-25
  69. 69. Gray LR, Tompkins SC, Taylor EB. Regulation of pyruvate metabolism and human disease. Cellular and Molecular Life Sciences. 2014;71(14):2577-2604
  70. 70. Dey P, Baddour J, Muller F, Wu CC, Wang H, Liao WT, et al. Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer. Nature. 2017;542(7639):119-123
  71. 71. Jolma A, Yin Y, Nitta KR, Dave K, Popov A, Taipale M, et al. DNA-dependent formation of transcription factor pairs alters their binding specificity. Nature. 2016;527(7578):384-388
  72. 72. Wolters S, Schumacher B. Genome maintenance and transcription integrity in aging and disease. Frontiers in Genetics. 2013;4:19
  73. 73. Pohjoismäki JLO, Boettger T, Liu Z, Goffart S, Szibor M, Braun T. Oxidative stress during mitochondrial biogenesis compromises mtDNA integrity in growing hearts and induces a global DNA repair response. Nucleic Acids Research. 2012;40(14):6595-6607
  74. 74. Kazak L, Reyes A, Holt IJ. Minimizing the damage: Repair pathways keep mitochondrial DNA intact. Nature Reviews. Molecular Cell Biology. 2012;13(11):659-671
  75. 75. Rehmani I, Liu F, Liu A. Chemistry, mechanisms, and disease pathogenesis. In: Villamena FA, editor. Molecular Basis of Oxidative Stress. Hoboken, NJ: John Wiley & Sons; 2013. p. 179-201
  76. 76. Gut P, Verdin E. The nexus of chromatin regulation and intermediary metabolism. Nature. 2013;502(7472):489-498
  77. 77. Liu J, Kim J, Oberdoerffer P. Metabolic modulation of chromatin: Implications for DNA repair and genomic integrity. Frontiers in Genetics. 2013;4:182
  78. 78. Uchiumi F, Shoji K, Sasaki Y, Sasaki M, Sasaki Y, Oyama T, et al. Characterization of the 5′-flanking region of the human TP53 gene and its response to the natural compound, Resveratrol. Journal of Biochemistry. 2016;159(4):437-447
  79. 79. Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, et al. Sirtuin activators mimic caloric restriction and delay aging in metazoans. Nature. 2004;430(7000):686-689
  80. 80. Park SJ, Ahmad F, Philp A, Baar K, Williams T, Luo H, et al. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell. 2012;148(3):421-433
  81. 81. Gueguen N, Desquiret-Dumas V, Leman G, Chupin S, Baron S, Nivet-Antoine V, et al. Resveratroldirectly binds to mitochondrial complex I and increases oxidative stress in brain mitochondria of aged mice. PLoS One. 2015;10(12):e0144290
  82. 82. Di LJ, Fernandez AG, de Siervi A, Longo DL, Gardner K. Transcriptional regulation of BRCA1 expression by a metabolic switch. Nature Structural & Molecular Biology. 2010;17(12):1406-1413
  83. 83. Chinnadurai G. CtBP, an unconventional transcription corepressor in development and oncogenesis. Molecular Cell. 2002;9(2):213-224
  84. 84. Chinnadurai G. The transcription corepressor CtBP: A foe of multiple tumor suppressors. Cancer Research. 2009;69(3):731-734
  85. 85. Gibson BA, Zhang Y, Jiang H, Hussey KM, Shrimp JH, Lin H, et al. Chemical genetic discovery of PARP targets reveals a role for PARP-1 in transcription elongation. Science. 2016;353(6294):45-50
  86. 86. Wright RH, Lioutas A, Le Dily F, Soronellas D, Pohl A, Bonet J, et al. ADP-ribose-derived nuclear ATP synthesis by NUDIX5 is required for chromatin remodeling. Science. 2016;352(6290):1221-1225
  87. 87. Porporato PE, Payen VL, Baselet B, Sonveaux P. Metabolic changes associated with tumor metastasis, part 2: Mitochondria, lipid and amino acid metabolism. Cellular and Molecular Life Sciences. 2016;73(7):1349-1363
  88. 88. Gentric G, Mieulet V, Mechta-Grigoriou F. Heterogeneity in cancer metabolism: New concepts in an old field. Antioxidants & Redox Signaling. 2017;26(9):462-485
  89. 89. Lord CJ, Ashworth A. PARP inhibitors: Synthetic lethality in the clinic. Science. 2017;355(6330):1152-1158
  90. 90. Li J, Bonkowski MS, Moniot S, Zhang D, Hubbard BP, Ling AJY, et al. A conserved NAD+ binding pocket that regulates protein-protein interactions during aging. Science. 2017;355(6331):1312-1317
  91. 91. Gorbunova V, Seluanov A, Mao Z, Hine C. Changes in DNA repair during aging. Nucleic Acids Research. 2007;35(22):7466-7474
  92. 92. Kraus WL, Lis JT. PARP goes transcription. Cell. 2003;113(6):677-683
  93. 93. Luo X, Ryu KW, Kim DS, Nandu T, Medina CJ, Gupte R, et al. PARP-1 controls the adipogenic transcriptional program by PARylating C/EBPβ and modulating its transcriptional activity. Molecular Cell. 2017;65(2):260-271
  94. 94. Ke Y, Han Y, Guo X, Wen J, Wang K, Jiang X, et al. PARP1 promotes gene expression at the post-transcriptional level by modulating the RNA-binding protein HuR. Nature Communications. 2017;8:14632
  95. 95. Lu J, Zhang R, Hong H, Yang Z, Sun D, Sun S, et al. The poly(ADP-ribosyl)ation of FoxO3 mediated by PARP1 participates in isoproterenol-induced cardiac hypertrophy. Biochimica et Biophysica Acta. 2016;1863(12):3027-3039
  96. 96. McDevitt MA. Clinical applications of epigenetics. In: Fraga M, Fernández AF, editors. Epigenomics in health and disease. San Diego, CA: Academic Press; 2016. p. 271-295
  97. 97. Suvà ML, Riggi N, Bernstein BE. Epigenetic reprogramming in cancer. Science. 2013;339(6127):1567-1570
  98. 98. Blakey CA, Litt MD. Epigenetic gene expression-an introduction. In: Huang S, Litt MD, Ann Blakey C, editors. Epigenetic Gene Expression and Regulation. San Diego, CA: Academic Press; 2016. p. 1-19
  99. 99. Hentze MW, Preiss T. The REM phase of gene regulation. Trends in Biochemical Sciences. 2010;35(8):423-426
  100. 100. Verdin E. NAD+ in aging, metabolism, and neurodegeneration. Science. 2015;350(6265):1208-1213
  101. 101. Pearce EL, Poffenberger MC, Chang CH, Jones RG. Fueling immunity: Insights into metabolism and lymphocyte function. Science. 2013;342(6155):1242454
  102. 102. Tanuma S, Johnson GS. ADP-ribosylation of nonhistone high mobility group proteins in intact cells. The Journal of Biological Chemistry. 1983;258(7):4067-4070
  103. 103. Tanuma S, Johnson LD, Johnson GS. ADP-ribosylation of chromosomal proteins and mouse mammary tumor virus gene expression. The Journal of Biological Chemistry. 1983;258(24):15371-15375
  104. 104. Ogata N, Ueda K, Hayaishi O. ADP-ribosylation of histone H2B. Identification of glutamic acid residue 2 as the modification site. The Journal of Biological Chemistry. 1980;255(16):7610-7615
  105. 105. Ogata N, Ueda K, Kagamiyama H, Hayaishi O. ADP-ribosylation of histone H1. Identification of glutamic acid residue 2, 14, and the COOH-terminal lysine residue as modification sites. The Journal of Biological Chemistry. 1980;255(16):7616-7620
  106. 106. Yu W, Ginjala V, Pant V, Chernukhin I, Whitehead J, Docquier F, et al. Poly(ADP-ribosyl)ation regulates CTCF-dependent chromatin insulation. Nature Genetics. 2004;36(10):1105-1110
  107. 107. Klenova E, Ohlsson R. Poly(ADP-ribosyl)ation and epigenetics. Is CTCF PARt of the plot? Cell Cycle. 2005;4(1):96-101
  108. 108. Han D, Chen Q, Shi J, Zhang F, Yu X. CTCF participates in DNA damage response via poly(ADP-ribosyl)ation. Scientific Reports. 2017;7:43530
  109. 109. Reale A, Matteis GD, Galleazzi G, Zampieri M, Caiafa P. Modulation of DNMT1 activity by ADP-ribose polymers. Oncogene. 2005;24(1):13-19
  110. 110. Caiafa P, Guastafierro T, Zampieri M. Epigenetics: Poly(ADP-ribosyl)ation of PARP-1 regulates genomic methylation patterns. The FASEB Journal. 2009;23(3):672-678
  111. 111. Martin KA, Cesaroni M, Denny MF, Lupey LN, Tempera I. Global transcriptome analysis reveals that poly(ADP-ribose) polymerase 1 regulates gene expression through EZH2. Molecular and Cellular Biology. 2015;35(23):3934-3944
  112. 112. Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, et al. Role of histone H3 lysine 27 methylation in polycomb-group silencing. Science. 2002;298(5595):1039-1043
  113. 113. Vijg J. From genome to phenome. In: Vijg J, editor. Aging of the Genome. The Dual Role of DNA in Life and Death. New York, NY: Oxford University Press; 2007. p. 233-288
  114. 114. Grube K, Bürkle A. Poly(ADP-ribose) polymerase activity in mononuclear leukocytes of 13 mammalian species correlates with species-specific life span. Proceedings of the National Academy of Sciences of the United States of America. 1992;89(24):11759-11763
  115. 115. Houtkooper RH, Pirinen E, Auwerx J. Sirtuins as regulators of metabolism and healthspan. Nature Reviews. Molecular Cell Biology. 2012;13(4):225-238
  116. 116. Neidhart M. DNA methylation and epigenetic biomarkers in cancer. In: Neidhart M, editor. DNA Methylation and Complex Human Disease. San Diego, CA: Academic Press; 2016. p. 9-27
  117. 117. Neidhart M. DNA methylation in metabolic diseases. In: Neidhart M, editor. DNA Methylation and Complex Human Disease. San Diego, CA: Academic Press; 2016. p. 201-214
  118. 118. Neri F, Rapelli S, Krepelova A, Incarnato D, Parlato C, Basile G, et al. Intragenic DNA methylation prevents spurious transcription initiation. Nature. 2017;543(7643):72-77
  119. 119. Hu X, Chen Y, Zhao ZJ. Structure, regulation, and function of TET family proteins. In: Huang S, Litt MD, Ann Blakey C, editors. Epigenetic Gene Expression and Regulation. San Diego, CA: Academic Press; 2016. p. 379-395
  120. 120. Thienpont B, Steinbacher J, Zhao H, D’Anna F, Kuchnio A, Ploumakis A, et al. Tumor hypoxia causes DNA hyper-methylation by reducing TET activity. Nature. 2016;537(7618):763-768
  121. 121. Yin Y, Morgunova E, Jolma A, Kaasinen E, Sahu B, Khund-Sayeed S, et al. Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science. 2017;356(6337):aaj2239
  122. 122. Almeida LO, Neto MPC, Sousa LO, Tannous MA, Curti C, Leopoldino AM. SET oncoprotein accumulation regulates transcription through DNA methylation and histone hypoacetylation. Oncotarget. 2017;8(16):26802-26818
  123. 123. Zykovich A, Hubbard A, Flynn JM, Tarnopolsky M, Fraga MF, Kerksick C, et al. Genome-wide DNA methylation changes with age in disease-free human skeletal muscle. Aging Cell. 2014;13(2):360-366
  124. 124. Florath I, Butterbach K, Müller H, Bewerunge-Hudler M, Brenner H. Cross-sectional and longitudinal changes in DNA methylation with age: An epigenome-wide analysis revealing over 60 novel age-associated CpG sites. Human Molecular Genetics. 2014;23(5):1186-1201
  125. 125. Tang M, Luo H, Lu J. Genetically altered cancer epigenome. In: Huang S, Litt MD, Ann Blakey C, editors. Epigenetic Gene Expression and Regulation. San Diego, CA: Academic Press; 2016. p. 265-289
  126. 126. Youn HD. Methylation and demethylation of DNA and histones in chromatin: The most complicated epigenetic marker. Experimental & Molecular Medicine. 2017;49(4):e321
  127. 127. Choudhary C, Weinert BT, Nishida Y, Verdin E, Mann M. The growing landscape of lysine acetylation links metabolism and cell signalling. Nature Reviews. Molecular Cell Biology. 2014;15(8):536-550
  128. 128. Verdin E, Ott M. 50 years of protein acetylation: From gene regulation to epigenetics, metabolism and beyond. Nature Reviews. Molecular Cell Biology. 2015;16(4):258-264
  129. 129. Blakey CA, Litt MD. Histone modifications-models and mechanisms. In: Huang S, Litt MD, Ann Blakey C, editors. Epigenetic Gene Expression and Regulation. San Diego, CA: Academic Press; 2016. p. 21-42
  130. 130. Yan B, Li X, Johnson A, Yang Y, Jian W, Qui Y. Epigenetic drugs for cancer therapy. In: Huang S, Litt MD, Blakey CA, editors. Epigenetic Gene Expression and Regulation. San Diego, CA: Academic Press; 2016. p. 397-423
  131. 131. Chung JH, Manganiello V, Dyck JR. Resveratrol as a calorie restriction mimetic: Therapeutic implications. Trends in Cell Biology. 2012;22(10):546-554
  132. 132. Roth GS, Ingram DK. Manipulation of health span and function by dietary caloric restriction mimetics. Annals of the New York Academy of Sciences. 2016;1363:5-10
  133. 133. Uchiumi F, Arakawa J, Takihara Y, Akui M, Ishibashi S, Tanuma S. The effect of trans-resveratrol on the expression of the human DNA-repair associated genes. International Journal of Molecular Medicine. 2016;3(5):783-792
  134. 134. Fang EF, Scheibye-Knudsen M, Chua KF, Mattson MP, Croteau DL, et al. Nuclear DNA damage signaling to mitochondria in aging. Nature Reviews. Molecular Cell Biology. 2016;17(5):308-321
  135. 135. Quiros PM, Mottis A, Auwerx J. Mitonuclear communication in homeostasis and stress. Nature Reviews. Molecular Cell Biology. 2016;17(4):213-226
  136. 136. Ku C, Nelson-Sathi S, Roettger M, Sousa FL, Lockhart PJ, Bryant D, et al. Endosymbiotic origin and differential loss of eukaryotic genes. Nature. 2015;524(7566):427-432
  137. 137. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Cancer genome landscapes. Science. 2013;339(6127):1546-1558
  138. 138. Tait SW, Green DR. Mitochondria and cell death: Outer membrane permeabilization and beyond. Nature Reviews. Molecular Cell Biology. 2010;11(9):621-632
  139. 139. Estaquier J, Vallette F, Vayssiere JL, Mignotte B. The mitochondrial pathways of apoptosis. In: Scatena R, Bottoni P, Giardina B, editors. Advances in Mitochondrial Medicine. Dordrecht, Germany: Springer Science+Business Media BV; 2012. p. 157-183
  140. 140. Kroemer G. Mitochondrial implication in apoptosis. Towards an endosymbiont hypothesis of apoptosis evolution. Cell Death and Differentiation. 1997;4(6):443-456
  141. 141. Galluzzi L, Kepp O, Kroemer G. Mitochondria: Master regulators of danger signaling. Nature Reviews. Molecular Cell Biology. 2012;13(12):780-788
  142. 142. Shankar S, Chen Q, Sarva K, Siddiqui I, Srivastava RK. Sensitization of TRAIL-resistant LNCaP cells by resveratrol (3, 4′, 5 tri-hydroxystilbene): Molecular mechanisms and therapieutic potential. Journal of Molecular Signaling. 2007;2:7
  143. 143. Shankar S, Siddiqui I, Srivastava RK. Molecular mechanisms of resveratrol (3,4,5-trihydroxy-trans-stilbene) and its interaction with TNF-related apoptosis inducing ligand (TRAIL) in androgen-insensitive prostate cancer cells. Molecular and Cellular Biochemistry. 2007;304(1-2):273-285
  144. 144. Venkatadri R, Muni T, Iyer AK, Yakisich JS, Azad N. Role of apoptosis-related miRNAs in resveratrol-induced breast cancer cell death. Cell Death Disease. 2016;7:e2104
  145. 145. Vousden KH, Lane DP. p53 in health and disease. Nature Reviews. Molecular Cell Biology. 2007;8(4):275-283
  146. 146. Vousden KH, Ryan KM. p53 and metabolism. Nature Reviews. Cancer. 2009;9(10):691-700
  147. 147. Green DR, Kroemer G. Cytoplasmic functions of the tumor suppressor p53. Nature. 2009;458(7242):1127-1130
  148. 148. King MC. “The race” to clone BRCA1. Science. 2014;343(6178):1462-1465
  149. 149. Sharma NK, Lebedeva M, Thomas T, Kovalenko OA, Stumpf JD, Shadel G, et al. Intrinsic mitochondrial DNA repair defects in Ataxia Telangiectasia. DNA Repair (Amst). 2014;13:22-31
  150. 150. Whatcott CJ, Meyer-Ficca ML, Meyer RG, Jacobson MK. A specific isoform of poly(ADP-ribose) glycohydrolase is targeted to the mitochondrial matrix by a N-terminal mitochondrial targeting sequence. Experimental Cell Research. 2009;315(20):3477-3485
  151. 151. Rossi MN, Carbone M, Mostocotto C, Mancone C, Tripodi M, Maione R, et al. Mitochondrial localization of PARP-1 requires interaction with mitofilin and is involved in the maintenance of mitochondrial DNA integrity. The Journal of Biological Chemistry. 2009;284(46):31616-31624
  152. 152. Moiseeva O, Bourdeau V, Roux A, Deschênes-Simard X, Ferbeyre G. Mitochondrial dysfunction contributes to oncogene-induced senescence. Molecular and Cellular Biology. 2009;29(16):4495-4507
  153. 153. Mohan V, Madhusuden S. DNA base excision repair: Evolving biomarkers for personalized therapies in cancer. In: Chen C, editor. New Research Directions in DNA Repair. Rijeka, Croatia: InTechOPEN; 2013. p. 529-557
  154. 154. Liu G, Kamp DW. Mitochondrial DNA damage: Role of Ogg1 and aconitase. In: Kruman I, editor. DNA Repair. Rijeka, Croatia: InTechOPEN; 2011. p. 85-102
  155. 155. Kim SJ, Cheresh P, Williams D, Cheng Y, Ridge K, Schumacker PT, et al. Mitochondria-targeted Ogg1 and aconitase-2 prevent oxidant-induced mitochondrial DNA damage in Alveolar Epithelial cells. The Journal of Biological Chemistry. 2014;289(9):6165-6176
  156. 156. Ceccaldi R, Sarangi P, D’Andrea AD. The Fanconi anaemia pathway: New players and new functions. Nature Reviews. Molecular Cell Biology. 2016;17(6):337-349
  157. 157. Cappelli E, Cuccarolo P, Stroppiana G, Miano M, Bottega R, Cossu V, et al. Defects in mitochondrial energetic function compels Fanconi Anaemia cells to glycolytic metabolism. Biochimica et Biophysica Acta. 2017;1863(6):1214-1221
  158. 158. Kamenisch Y, Fousteri M, Knoch J, von Thaler AK, Fehrenbacher B, Kato H, et al. Proteins of nucleotide and base excision repair pathways interact in mitochondria to protect from loss of subcutaneous fat, a hallmark of aging. The Journal of Experimental Medicine. 2010;207(2):379-390
  159. 159. Kim J, Hu Z, Cai L, Li K, Choi E, Faubert B, et al. CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells. Nature. 2017;546(7656):168-172
  160. 160. Sahin E, DePinho R. A axis of aging: Telomerase, p53 and mitochondria. Nature Reviews. Molecular Cell Biology. 2012;13(6):397-404
  161. 161. Cantó C, Menzies KJ, Auwerx J. NAD+ metabolism and the control of energy homeostasis: A balancing act between mitochondria and the nucleus. Cell Metabolism. 2015;22(1):31-53
  162. 162. Li D, Bi FF, Chen NN, Cao JM, Sun WP, Zhou YM, et al. A novel crosstalk between BRCA1 and poly(ADP-ribose) polymerase 1 in breast cancer. Cell Cycle. 2014;13(21):3442-3449
  163. 163. Cantó C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, et al. The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metabolism. 2012;15(6):838-847
  164. 164. Han X, Tai H, Wang X, Wang Z, Zhou J, Wei X, et al. AMPK activation protects cells from oxidative stress-induced senescence via autophagic flux restoration and intracellular NAD elevation. Aging Cell. 2016;15(3):416-427
  165. 165. Yang Y, Sauve AA. NAD+ metabolism: Bioenergetics, signaling and manipulation for therapy. Biochimica et Biophysica Acta. 2016;1864(12):1787-1800
  166. 166. Zhang H, Ryu D, Wu Y, Gariani K, Wang X, Luan P, et al. NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. 2016;352(6292):1436-1443
  167. 167. Yun J, Finkel T. Mitohormesis. Cell Metabolism. 2014;19(5):757-766
  168. 168. Mouchiroud L, Houtkooper RH, Auwerx J. NAD+ metabolism, a therapeutic target for age-related metabolic disease. Critical Reviews in Biochemistry and Molecular Biology. 2013;48(4):397-408
  169. 169. Seyfried TN, Flores RE, Poff AM, D’Agostino DP. Cancer as a metabolic disease: Implications for novel therapeutics. Carcinogenesis. 2013;35(3):515-527
  170. 170. Vyas S, Zaganjor E, Haigis MC. Mitochondria and cancer. Cell. 2016;166(3):555-566
  171. 171. Santidrian AF, Matsuno-Yagi A, Ritland M, Seo BB, LeBoeuf SE, Gay LJ, et al. Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. The Journal of Clinical Investigation. 2013;123(3):1068-1081
  172. 172. Tran MT, Zsengeller ZK, Berg AH, Khankin EV, Bhasin MK, Kim W, et al. PGC1α drives NAD biosynthesis linking oxidative metabolism to renal protection. Nature. 2016;531(7595):528-532
  173. 173. Luo C, Lim JH, Lee Y, Granter SR, Thomas A, Vazquez F, et al. PGC1α-mediated transcriptional axis suppresses melanoma metastasis. Nature. 2016;537(7620):422-426
  174. 174. Guarente L. Linking DNA damage, NAD+/SIRT1, and aging. Cell Metabolism. 2014;20(4):706-707
  175. 175. Bai P, Cantó C, Oudart H, Brunyanszki A, Cen Y, Thomas C, et al. PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metabolism. 2011;13(4):461-468
  176. 176. Baxter P, Chen Y, Xu Y, Swanson RA. Mitochondrial dysfunction induced by nuclear poly(ADP-ribose) polymerase-1: A treatable cause of cell death in stroke. Translational Stroke Research. 2014;5(1):136-144
  177. 177. Zhao Y, Butler EB, Tan M. Targeting cellular metabolism to improve cancer therapeutics. Cell Death & Disease. 2013;4:e532
  178. 178. Georgakilas AG, Redon CE, Ferguson NF, Kryston TB, Parekh P, Dickey JS, et al. Systemic DNA damage accumulation under in vivo tumor growth can be inhibited by the antioxidant Tempol. Cancer Letters. 2014;353(2):248-257
  179. 179. Khabour OF, Alzoubi KH, Mfady DS, Alasseiri M, Hasheesh TF. Tempol protects human lymphocytes from genotoxicity induced by cisplatin. International Journal of Clinical and Experimental Medicine. 2014;7(4):982-988
  180. 180. Yamato M, Kawano K, Yamanaka Y, Saiga M, Yamada K. TEMPOL increases NAD+ and improves redox imbalance in obese mice. Redox Biology. 2016;8:316-322
  181. 181. Chen G, Pelicano H, Ogasawara MA, Wang F, Huang P. Targeting mitochondria of cancer cells: Mechanisms and compounds. In: Neuzil J, Pervaiz S, Fulda S, editors. Mitochondria: The Anti-cancer Target for the Third Millenium. Dordrecht, Germany: Springer Science+Business Media BV; 2014. p. 183-210
  182. 182. Dong LF, Neuzil J. Vitamin E analogues as prototypic mitochondria-targeting anti-cancer agents. In: J. Neuzil, S. Pervaiz, S. Fulda, editors. Mitochondria: The Anti-cancer Target for the Third Millennium. Dordrecht, Germany: Springer Science+Business Media BV; 2014. p. 151-181
  183. 183. Halicka HD, Zhao H, Li J, Lee YS, Hsieh TC, Wu JM, et al. Potential anti-aging agents suppress the level of constitutive mTOR- and DNA damage-signaling. Aging. 2012;4(12):952-965
  184. 184. Chamoto K, Chowdhury PS, Kumar A, Sonomura K, Matsuda F, Fagarasan S, et al. Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity. Proceedings of the National Academy of Sciences of the United States of America. 2017;114(5):E761-E770
  185. 185. Keckesova Z, Donaher JL, De Cock J, Freinkman E, Lingrell S, Bachovchin DA, et al. LACTB is a tumor suppressor that modulates lipid metabolism and cell state. Nature. 2017;543(7647):681-686
  186. 186. Pagliarini DJ, Calvo SE, Chang B, Sheth SA, Vafai SB, Ong SE, et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell. 2008;134(1):112-123
  187. 187. Wang Y, Oxer D, Hekimi S. Mitochondrial function and lifespan of mice with controlled ubiquinone biosynthesis. Nature Communications. 2015;6:6393
  188. 188. Chen P, Yu J, Knecht J, Chen Q. Decrease of PDSS2 expression, a novel tumor suppressor, in non-small cell lung cancer. Cancer Epidemiology. 2013;37(2):166-171
  189. 189. Kanda M, Sugimoto H, Nomoto S, Oya H, Shimizu D, Takami H, et al. Clinical utility of PDSS2 expression to stratify patients at risk for recurrence of hepatocellular carcinoma. International Journal of Oncology. 2014;45(5):2005-2012
  190. 190. Titov DV, Cracan V, Goodman RP, Peng J, Grabarek Z, Mootha VK. Complementation of mitochondrial electron transport chain by manipulation of the NAD+/NADH ratio. Science. 2016;352(6282):231-235
  191. 191. Yang ZF, Drumea K, Mott S, Wang J, Rosmarin AG. GABP transcription factor (nuclear respiratory factor 2) is required for mitochondrial biogenesis. Molecular and Cellular Biology. 2014;34(17):3194-3201
  192. 192. Bose R, Karthaus WR, Armenia J, Abida W, Iaquinta PJ, Zhang Z, et al. ERF mutations reveal a balance of ETS factors controlling prostate oncogenesis. Nature. 2017;546(7660):671-675

Written By

Fumiaki Uchiumi, Jun Arakawa, Yutaka Takihara, Motohiro Akui, Hiroshi Hamada and Sei-ichi Tanuma

Submitted: 15 March 2017 Reviewed: 20 September 2017 Published: 20 December 2017