Duplicated GGAA motifs in the 5’-upstream regions of human DNA-repair associated genes
A variety of transcription factor binding sequences instead of the authentic TATA- or TATA-like elements are present in large numbers of 5’-flanking or regulatory regions of the human genes . Our previous research showed that several human gene promoter regions of the DNA repair-associated genes, including
The molecular mechanisms of effect induced by caloric restriction (CR) mimetic drugs, including Resveratrol (Rsv), have been well studied . It was suggested that the CR mimetic compounds activate NAD+ dependent deacetylase sirtuins, or inhibits cAMP phosphodiesterases to improve mitochondrial functions . Thus, it is supposed that Rsv affects cellular senescence to elongate lifespan of various organisms . It should be noted that mitochondrial functions cross-talk with telomeres in which telomere-shortening causes chromosomal instability and leads to cellular senescence . We have reported that caloric restriction (CR) mimetics, 2-deoxy-D-glucose (2DG) and Rsv up-regulate promoter activities of the 5’-flanking regions of genes encoding telomere-maintenance factors including shelterin complex proteins . Moreover, we observed that telomerase activity in HeLa S3 cells was moderately induced by the 2DG and Rsv [7,8]. Additionally, it has been reported that tumor suppressor p53, which is encoded by the
In this review article, we will discuss the contribution of
2. Transcription of eukaryotic cells
2.1. General transcription factors and TATA-dependent and independent transcription mechanisms
Transcription or synthesis of RNAs is known to be regulated at several steps, including chromosomal modification, transcription initiation, elongation, and termination . Eukaryotic transcription of mRNAs is catalyzed by RNA polymerase II (Pol II) and the molecular mechanisms are well studied . Initiation of transcription is executed by transcription machinery complex consisting of Pol II and general transcription factors (GTFs), such as TFIIA, TFIIB, TFIID, TFIIE, TFIIF, and THIIH. Transcription is thought to start from the formation of pre-initiation complex (PIC), which contains GTFs and Pol II, at the transcription start site (TSS) . The most studied eukaryotic promoter regions contain TATA- or TATA-like sequences that are recognized by TATA binding protein (TBP). Binding of TBP to the TATA-box results in recruitment of TFIID and TAFs , then it provokes the formation of the PIC, precisely determining the TSS. Although TATA-dependent transcription initiating mechanisms have been extensively characterized by a variety of experiments, 76% of the TSSs in human genomes have no obvious TATA or TATA-like elements . This fact clearly indicates that eukaryotic transcription is initiated by either TATA-dependent or independent mechanisms.
2.2. TATA-less promoters-genome wide analyses by ChIP experiment
Recent study of PICs in
3. Promoter regions of the human DNA-repair associated genes
We have been studying the regulatory mechanism of the human
Poly(ADP-ribosyl)ation is thought to be involved in the process of DNA-repair, which is dependent on both poly(ADP-ribose) synthesis and degradation . Given that the
3.1. Surveillance of 5’-upstream regions of the PARP and PAR-associated protein encoding genes
At first, we understood that the duplicated GGAA is a sequence that should be associated with macrophage-like differentiation of HL-60 cells induced by 12-
PARP modifies itself and various target proteins by addition of a PAR using NAD+ as the substrate . This modification is important for the recruitment of base excision repair (BER) associating factors, including XRCC1 . Therefore, expression of the genes encoding PARP target proteins or PAR-associating proteins might be similarly regulated as in
PARP1 has been reported to regulate G1 arrest in response to DNA damage
3.2. Surveillance of the DNA repair associated gene promoter regions
XRCC1, which is a 70-kDa X-ray cross-complementing group 1 protein, is thought to act as a scaffold protein for BER and DNA single strand break repair (SSBR) . Various proteins are involved in the XRCC1-associated DNA-repair processes, including APEX1 (APE1), TDP1, PCNA, RFC, POLB (DNA-pol β), WRN, ERCC6 (CSB), and E2F family proteins . We previously reported that the
Additionally, GGAA-duplications around the TSSs of the human
3.3. Possible roles of the duplicated GGAA motif in the 5’-upstream regions of DNA-repair genes as a bidirectional initiation element
It has been shown that the human
3.4. Multiplicity of GGAA motifs may play a role in the formation of specific chromosomal structures
It is well known that various repetitive sequences are providing special features at specific regions of eukaryotic chromosomes. Telomeres are composed of TTAGGG repeats and they are maintained by specific structures that are known as T- and D-loops . Other example is that the centromeres, in which the (CENP) B box is located, have specific structures that function to segregate chromosomes accurately . Interestingly, the 17-bp sequence of (CENP) B box, which is recognized by CENP-B protein, contains GGAA motif, and this (CENP) B box appear every other α-satellite repeat (171-bp sequence) in human chromosomes [37,38]. Thus, repetitive sequences play roles in the formation of specific chromosomal structures and they are generally referred as microsatellites.
It is noteworthy that repetitive GGAA motifs or GGAA-microsatellites are targets of the oncogenic fusion protein EWS/FLI, whose mRNA is transcribed from the result of aberrant chromosomal translocation, t(11;22)(q24;q12) [39,40]. The GGAA-microsatellites are located in the promoter regions of several genes, including
4. Promoter regions of the human telomere maintenance factor-encoding genes
Human telomeres are unique structures of chromosomal ends where telomere binding proteins and telomere maintenance factors are associated to control chromosomal integrity, and their shortening is thought to cause instability of chromosomes leading to cellular senescence [35,47]. It has been shown that telomeres form a T-loop configuration [47,48], which are protected by shelterin proteins, including TRF1, TRF2, Rap1, TIN2, TPP1 and POT1 [49,50]. Recently, conditional knock down experiments demonstrated that shelterin proteins function as repressors or inhibitors of ATM/ATR signaling, non-homologous end joining (NHEJ), alt-NHEJ, HRR and resection . Given that shelterin proteins have similar functions in protecting telomeres from DNA-damage, shelterin genes might be regulated in a similar manner to each other. In addition, their gene expression needs to be regulated by a unique system that is different from those of ATM/ATR signaling, NHEJ, alt-NHEJ, HRR and resection.
4.1. GC-box or Sp1 binding element is a common TF binding motif within the 5’-upstreams of the telomere maintenance factor-encoding genes
Previously, we have isolated 300 to 500-bp 5’-upstream regions of the human
4.2. TATA-independent regulatory mechanisms of DNA-repair associated genes and telomere maintenance factor-encoding genes
Clustering analysis of TF-binding sites in human promoters revealed that a TATA-box is totally absent in promoters containing an ETS binding motif . The most frequently found sequence co-localized with ETS binding motifs in human promoters is the Sp1 element with 28.4% occurrence , next is the ETS binding motif itself (18.7%). In addition, occurrences of Sp1 motif with the other Sp1 motifs in human promoters was estimated at 61.2%. These lines of evidences suggest that Sp1 family and ETS family proteins synergistically control promoters containing both elements.
However, comparison of common TF-binding motifs in the 5’-flanking regions of the DNA-repair and telomere associated genes suggest that they are individually regulated by GGAA-binding factors and GC-box-binding factors, respectively. In addition, most of these promoters do not have an authentic TATA or TATA-like element. We can speculate that through the evolution of organisms, GGAA-duplicated motifs have become selectively utilized for regulation of gene expression of the DNA-repair factor encoding genes, while GC-box might have developed to be a regulator for telomere maintenance factor-encoding genes (Fig. 1). TATA-dependent transcription may have been disadvantageous in control of DNA damage inducible genes with a distinct ability to sustain or maintain integrity of genomes, including chromosomes and telomeres.
5. Caloric restriction induced signals that affect transcription of the telomere associated genes
It is well established that loss of function mutations on the
5.1. Effect of CR mimetic drugs on telomere associated protein-encoding gene promoters
2DG and Rsv, which are known as a potent inhibitors of glucose metabolism , and an activator of sirtuin-mediated deacetylation , respectively, are referred as CR mimetic drugs. It has been shown that telomerase activity in HeLa S3 cells was moderately activated by 2DG and by Rsv [7,8]. These observations suggest that CR mimetic drugs have protective effects on telomeres by inducing telomerase activity along with up-regulating expression of the telomere maintenance factor-encoding genes. Up to present, human
Interestingly, both duplicated GGAA-motif and GC-boxes are contained within 500-bp upstream of the TSS of the human
5.2. Mechanisms that regulate aging or lifespan
viamitochondria and metabolic stress
Genetic studies of
It has been shown that mitochondrial functions can control lifespan . Furthermore, it was suggested that a cross talk system between telomeres and mitochondria functions in the regulation of aging . This concept was implied from a
Here we discussed the TF-binding elements in the 5’-upstream regions of DNA-repair factor- and telomere maintenance factor-encoding genes, and proposed that duplicated GGAA in conjugation with the GC-box/Sp1-regulatory motifs are common sequences required for their gene regulation (Table 1). Moreover, duplicated GGAA-motifs are frequently found in the bidirectional promoter regions of head-dead oriented DNA-repair genes (Table 2). GGAA containing sequences are known as a target for ETS family proteins, and the GC-box can be recognized by multiple proteins, including Sp1 family. Therefore, multiple TFs may access and bind to the duplicated GGAA or GC-box when cells were exposed to DNA damage or energy stress (Fig. 1). Therefore, we hypothesize that these genes are required to respond promptly and accurately when cells encounter stress signals, such as DNA damage or lack of energy source. This might in part explain why they have common
The authors are grateful to Takahiro Oyama and Midori Konno for discussion and outstanding technical assistance. This work was supported in part by a Research Fellowship from the Research Center for RNA Science, RIST, Tokyo University of Science.
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