BRCA Biological Functions

Abstract

BRCA1 and BRCA2 genes encode proteins that have important roles in DNA repair and act as tumor suppressors. Though the sequence and structure of the proteins produced by BRCA1 and BRCA2 are different, they have similar biological activities. Both BRCA gene products are reported to interact with the RAD51 protein, which is essential for DNA repair through homologous recombination. BRCA gene mutations are associated with an increased risk of solid tumors. Their ubiquitously expressed protein products are involved in essential cellular functions. The defect caused by BRCA gene mutations might be leveraged to develop new targeted cancer treatments. This chapter outlines that BRCA1 and BRCA2 have unique roles in the pathways leading to DNA double-strand break repair and clinical findings show that BRCA genes play a crucial role in a variety of biological processes.

1. Introduction

Mutations in the tumor suppressor genes BRCA1 (breast cancer susceptibility gene 1) and BRCA2 have an impact on various types of cancer (breast cancer susceptibility gene 2). More than 20 years ago, researchers first discovered an association between the BRCA1 and BRCA2 genes and the risk of developing ovarian and breast cancer [1]. Stomach, prostate, pancreatic, and colorectal cancers also have been linked to genetic mutations in the BRCA gene. There is some evidence that familial ovarian and breast cancers are linked to pancreatic, stomach, and prostate cancers via mutation, which accounts for 20% of these cancers [2].

While homologous recombination mends precise DNA damage, the BRCA1 and BRCA2 proteins are vital for the process [3]. This helps to ensure that the genome retains its complete and unaltered state. Depletion of BRCA capabilities consequences in genomic instability, which further drives the oncogenic conversion of non-tumorigenic cells into tumor-initiating cells, also referred to as cancer stem cells (CSCs), and further tumorigenesis. Several investigations over the last decade have shown that cancer cells within a single tumor varied significantly in terms of their potential to initiate tumors. A CSC population is capable of long-term self-renewal and differentiation into various tumor cell types and development. In addition to the prominent genomic imbalance/instability that is connected to tumor tissues, CSCs also have a high ability to self-renew and clonogenic potential, which suggests that they may act as a catalyst for the growth of cancer [4]. consequently, intratumoral heterogeneity is contingent on the CSC’s development, which is represented by the with-in quantity of newly forming tumor replicates [5].

In this chapter, we discuss the interaction between the BRCA gene and the RAD51 protein, which is important for DNA repair via homologous recombination, as well as the clinical significance and the central function of BRCA genes in a variety of biological functions.

2. BRCA genes and encoded proteins

The basic sequences of BRCA1 and BRCA2 are significantly diverse. BRCA1 (with 17q21, 17 chromosomes: 43,044,294 to 43,125,482base pairs) happens to be a 24-exon protein containing 1863 amino acids. It’s made up of several domains for distinct purposes. It has the zinc-finger binding domain RING (Quite Fascinating New Gene) at the N-terminus, which is required for BRCA1 and BARD1 interaction and E3 ubiquitin ligase complex formation [6]. ABRAXAS, BRIP1/FACJ, CtIP, and 2 Phosphopeptide-binding BRCT (BRCA1 C-terminal) dominions mediate the association between BRCA1 and also its associated proteins (Figure 1). Exons 11–13, which encode the central region of BRCA1, are often mutated in patients with breast cancer. 2 Nuclear localization signals (NLS) along with 1 coiled-coil domain are required for the interaction of BRCA2 via PALB2 [7].

Figure 1.

Schematic representation of BRCA1 and BRCA2 proteins. BRCA1 has 23 exons and 1863 amino acids, whereas BRCA2 has 27 exons and 3418 amino acids. BRCA1 contains a highly conserved zinc-binding RING (very intriguing new gene) finger domain near the N-terminus. Two BRCT (BRCA1 C-terminal) domains are located at the C-terminus. The core region of BRCA1 is made up of two NLS (nuclear localization signals) and one coiled-coil domain. BRCA2 has eight BRC repetitions of 20–30 amino acids. BRCA2 features a TAD (transcriptional activation domain) domain at its amino-terminus and two NLS and one TR2 domain at its carboxyl-terminus. The DNA-binding domain lies at the C-terminus and consists of a helical domain (H), three oligonucleotide-binding (OB) folds, and a tower domain (T). The domain names are displayed above. Braces are used to designate exons. Below are noted the locations of founder mutations.

The BRCA1 gene has more than 1600 mutations, involving omissions, infusions, and single nucleotide mutations have been identified [8]. The majority of BRCA1 mutations have been detected in BRCT as well as RING dominions, in addition to exons from 11 to 13, that encode the NLS necessary for BRCA1 operations, then act as complex formation sites for additional BRCA1-interacting proteins, such as c-Myc, Rad50, Rad51, pRb, BRCA2 and PALB2 [9]. Ashkenazi Jews have a 5382insC frameshift alteration that appeared in Scandinavia and Russia, as well as 185delAG founder alterations in the RING and BRCT domains [10]. Mutations in BRCA1 exons 11–13 are linked with ovarian cancer and the breast to develop pancreatic, colon, rectal, and stomach cancer [11].

BRCA2 is an enormous protein that consists of around 3418 different amino acids and is located on chromosome 13 at position 13q12.3 (base pairs 32,315,479 to 32,399,671). Its genomic data accounts for about 84.2 kb and has 27 exons. The transcriptional activation domain (TAD) is present on the N-terminus of BRCA2. Exon 11 encodes the middle region with eight RAD51-binding BRC repeats [12]. BRCA2’s carboxyl terminus features a DNA-binding domain made up of a tower domain (T), 3 oligonucleotide binding (OB) folds, as well as conserved helical dominion that makes it easier for BRCA2 to attach to double- and single-stranded DNA (ssDNA) (Figure 1). There are 2 NLS domains and 1 TR2 domain on the C terminus of BRCA2 [13]. It has about 1800 mutations. Frameshift replacements, erasures, and nonsense genetic mutations caused by these lesions result in untimely protein curtail or non-functional proteins [14]. Exon 11 of the BRCA2 gene encodes the most common germline frameshift mutation, 6174delT. BRCA2 mutations are connected to stomach, pancreatic, breast, ovarian, prostate, gall bladder, and bile duct cancer [15].

3. Interaction of RAD51 and the BRCA proteins

Amidst changes in order and structure, BRCA1 and BRCA2 share biological roles. BRCA1 and BRCA2 have comparable subcellular localization and expression patterns. Both are expressed during the cell cycle’s S phase, suggesting DNA replication responsibilities [16]. When DNA is damaged, two subnuclear foci change their distribution. Both proteins are found in synaptonemal complexes of meiotic axial filaments. This expression and localization pattern is paralleled by RAD51, a human counterpart of the bacterial protein RecA, which E. coli requires to repair double-strand breaks (DSBs) through genetic recombination. It’s been noted that RAD51 binds to both BRCA1 and BRCA2. In vitro, BRCA2-RAD51 interacts directly with recombinant protein fragments and the yeast two-hybrid system [17]. In yeast two-hybrid tests, murine BRCA2 binding to RAD51’s first 98 residues was mediated by a C-terminal motif. Human BRCA2 homologous region 95% similar to murine sequence does not bind RAD51 [18].

Eight BRC repeats mediate RAD51’s interaction with human BRCA2 [19]. With the exception of BRC5 and BRC6, each repetition can bind to RAD51 independently in two-hybrid experiments and in vitro when expressed as a GST fusion protein. BRC5 and BRC6 aren’t capable. In two-hybrid experiments, BRC4 binds RAD51 four times more than BRC1. PCR mutagenesis identifies a 30-residue binding consensus in BRC1 and BRC4. Despite this core motif, BRC1 and BRC4 require different residues for RAD51 binding. This shows that BRC1 and BRC4 interact differentially with RAD51 [20].

BRCA1’s interaction with RAD51 was first linked to a region covering residues 758–1064 [21]. Yet it is still unknown whether direct interaction between the two proteins is possible. Co-immunoprecipitated cell extracts show a low-stoichiometry interaction not confirmed by yeast two-hybrid or recombinant proteins. In meiotic and mitotic cells, BRCA1 and BRCA2 are co-localized. A region of BRCA1 (residues 1314–1863) that is unrelated to RAD51 binding is where these two proteins interact [17]. The connection may not be direct and involves 2–5% of each protein’s cellular pool. Current biochemical purification and mass spectrometry efforts to characterize the BRCA1 protein complex have not detected RAD51 or BRCA2 [22].

Therefore, of the identified physical interactions between BRCA1, BRCA2, and RAD51, the BRCA2-RAD51 contact seems to be the most well-established. Although the functional significance of their observed interactions has not yet been determined, existing data suggest that BRCA1 interacts with BRCA2, RAD51, and BRCA2 in a multimolecular complex.

4. Clinical relevance of BRCA genes

The link between BRCA1/2 domain functions and tumor growth has been studied in animal models, but clinical data are required [23]. Most BRCA gene mutations (70–80%) induce protein dysfunction or absence. Certain clinically important mutations enhance the risk of hereditary cancers [24]. In addition, numerous studies have found a correlation between BRCA1/2 mutations and aggressiveness of tumors, and inadequate clinical results in cancer patients. In a recent investigation of 603 cases of sporadic pancreatic cancer in China, it was found that the germline missense variant rs1799966 (c.4837A > G[p.Ser1613 Gly]) in the BRCT dominion of the BRCA1 gene was related to lower overall patient life expectancies [25].

Contradictory results have been found in clinical studies investigating a potential link between BRCA1 and BRCA2 mutations and the prognosis of patients with breast cancer. In a recent prospective multihospital investigation of 2733 young breast cancer patients, 388 had BRCA1/2 mutations. Overall survival did not differ between people with and without BRCA mutations. According to the analysis of 558 triple-negative breast cancer (TNBC) patients, BRCA1/2 alterations/mutation transferors outlived non-carriers overall [26]. In the same time frame, 202 invasive breast cancer patients from Japan who underwent a retrospective study discovered that a loss of heterozygosity (LOH) at the BRCA1 gene is connected to notable shorter disease-free endurance, remote metastasis-free survival, and overall endurance [27]. In yet another detailed overview, among 458 Chinese breast cancer patients with pathogenic germline BRCA2 mutations, lymph node metastases were more prevalent at diagnosis and had inferior results, such as disease-free life-span and distant relapse [28]. BRCA1 mutations enhance the prognosis for ovarian cancer, according to a meta-analysis of 33 scientific cases [29].

More prospective research on the impact of individual pathogenic mutations in tumor growth and patient responses to therapy is required to better understand how the prognosis of patients with ovarian and breast cancer is impacted by BRCA1/2 mutations. It may be possible to better target clinical treatment for BRCA-related malignancies by understanding the relationship between tumor aggressiveness and BRCA mutations.

5. Protective role of BRCA genes in the maintenance of genomic stability

Through the control of homologous recombination, the BRCA1 and BRCA2 proteins are crucial for DNA double-strand break (DSB) repair (HR) (Figure 2) [30]. Using a homologous template, such as sister chromatids, HR is a DNA repair technique that achieves high precision. If sister chromatids are present, they can be effective in S and G2. Pre-synapsis, post-synapsis, and synapsis are processes in DNA repair [31]. Initial DSB ends are cut during the first stage by the Mre11-RAD50-Nbs1 (MRN) complex as well as C-terminal binding protein interacting protein (CtIP) with nuclease activity, leaving a 3′- single strand (ss) DNA tail that replication protein A (RPA) protects from destruction. Next, BRCA1 and BRCA2 regulate the invasion of RAD51-ssDNA filament into homologous duplex DNA. A D-loop (displacement loop) structure is created when the third DNA strand spans between two double-stranded DNA molecules. The resulting nucleoprotein filament searches for a similar DNA sequence on the sister chromatid and enters a duplex to produce a mutual molecule. In the final stage, during post-synapsis, RAD51 separates from dsDNA. DNA polymerases stretch the damaged DNA’s 3′ end, followed by DNA ligation [32]. When DNA recombination results in Holliday junctions, the various mechanisms outlined elsewhere help resolve them, leading to an error-free repair [33].

Figure 2.

The precise role of BRCA1 and BRCA2 in DNA DSB repair. The BRCA protein fixes DNA double-strand breaks, halted replication forks, and DNA cross-links. Protein kinases like ataxia telangiectasia and Rad3 related (ATR) and ataxia telangiectasia mutant (ATM) that activate the pathways are able to detect DNA damage. The RAD51 recombinase, which is responsible for mediating homology-directed (HR) repair and strand invasion is regulated by BRCA2 via the MRN complex (RAD50-MRE11-NBS1).

Additionally, BRCA1 controls both HR-dependent DNA repair and non-homologous end joining (NHEJ) repair. NHEJ is a DNA repair process that ligates broken DNA ends without a template. HR takes longer but is error-free and accurate at rectification. Contrarily, DNA repair by NHEJ often causes mutations. It’s the fastest DNA DSB repair process. Classical (C) NHEJ occurs most often in G0 and G1 but in every phase. The process is broken down into three steps: break recognition, end-processing, and ligation. DNA-PK and NHEJ proteins are recruited when Ku70/Ku80 recognizes DSB ends. After that, DNA-PK recruits endonuclease Artemis to handle DSB ends. End ligation is promoted by the XRCC4 (X-ray repair cross-complementing protein 4)/Lig4 protein [34].

Unlike C-NHEJ, alternative (A)-NHEJ requires an MRN complex, CtIP, and poly (ADP-ribose) polymerase-1 (PARP-1) for protein recruitment and DNA lesion recognition. A-NHEJ is a backup repair route for C-NHEJ, but its mechanism is less well-known [35]. According to recent studies, dephosphorylating 53BP1 allows BRCA1 to switch from NHEJ to HR-dependent DNA repair (p53-binding protein 1) [36]. CDK phosphorylates CtIP at Ser327 when BRCA1, CtIP, and MRN activate HR [37]. PALB2/FANCN recruits BRCA2 at DNA DSB sites during HR via BRCA1 [38].

Extensive research has also been conducted on the role of BRCA2 in DSB repair. BRCA2 plays a key function in HR by recruiting RAD51 to DSBs [39]. BRCA2 deletion causes tumorigenesis and genomic instability. This is partly because BRCA2 regulates RAD51’s intracellular location and DNA-binding ability. The MRN complex recruits BRCA1 and CtIP to the DNA DSB site, which induces phosphorylation and ubiquitination. This complex promotes BRCA2 to DNA DSBs with Exo1 and DNA2-BLM (Bloom syndrome protein). BRCA2 recruits RAD51 to DNA damage sites, displacing RPA. BRCA2’s BRC repeats and TR2 domain allow RAD51 to load onto ssDNA and search for a DNA template [36]. BRCA2 may work with RAD51 paralogs XRCC2 and XRCC3 to assemble RAD51 with ssDNA [38]. It regulates stalled DNA replication by binding to RAD51 BRC repeats. BRCA2 inhibits MRE11 to prevent chromosomal defects during replication stalling [40] 3′-repair exonuclease 2 (TREX-2) complexes recruit BRCA2 to handle R-loops, which form during transcription from hybrid DNA-RNA and ssDNA [41].

6. Biological functions of the BRCA gene

6.1 Role of BRCA genes in the biological response to DNA damage and DNA double-strand break repair (DSB)

BRCA1 and BRCA2 co-localize DNA damage responses were inevitable. Studies on breast-cancer-susceptibility-gene-mutated cells support this. DNA damage triggers cell cycle checkpoints and DNA repair mechanisms. Inactivating DNA checkpoints or repair enhances genotoxicity. Due to increased X-ray sensitivity, BRCA1 and BRCA2 take part in a significant role in the response to DNA damage in murine cells [42, 43]. DSB repair, the X-ray radiation-induced lesion, was found to be defective in BRCA1 or BRCA2-deficient cells. NHEJ and homologous recombination repair DSBs in mammalian cells. NHEJ ligates DNA without end-sequence homology. DSBs can be repaired by exchanging DNA from damaged templates and sister chromatids. In mammalian cells, its mechanism is unknown. Yeast recombination depends on Rad51p, Rad52p, Rad54p, Rad55p, Rad57p, Rad59p, and Mre11p/Xrs2p-Rad50. These yeast genes have similar mammalian homologs [44].

Existing research shows that BRCA2 might not be required for DSB repair through NHEJ. The V(D)J reconfiguration of T cell receptors or antibodies, known as an NHEJ reaction, can occur if the mouse Brca2 gene is shortened [42]. BRCA2-deficient cells can perform DNA-PK-dependent NHEJ in vitro [45]. BRCA2 is essential for DSB repair by homologous recombination, according to recent, convincing data. Truncated Brca2 cells develop tri-radial and quadri-radial chromosomes in culture [42]. Radial features indicate Bloom’s syndrome and Fanconi’s anemia. BRCA2 deficiency hinders DNA-damaged RAD51 nuclear foci and repair sites [45].

BRCA1 and BRCA2 play different roles in DSB recombination. BRCA2 appears to play a direct role in this mechanism. BRCA2 may influence RAD51’s intracellular transport and function. BRCA2 may aid in the movement of RAD51 out of its synthesis site to its active position since RAD51, which lacks a nuclear localization signal, is poorly carried into the nucleus in cells with a defective form of the gene. Peptides BRC3, BRC4, or BRC7 suppress nucleoprotein filament formation in vitro. Gel filtration indicated that binding RAD51 to BRC peptides prevents filament multimerization. These data suggest that BRCA2-RAD51 cannot promote homologous recombination in vivo. These in-vitro data show that BRCA2 is necessary for DSB repair in vivo. The BRCA2-Rad51 complex may exist in two states in vivo: an inactive state that precludes Rad51 from adhering to single-strand DNA as well as an active state where Rad51 generates nucleoprotein filaments that BRCA2 can transfer. A structural change in the BRCA2-Rad51 interaction that releases Rad51 from BRCA2 may be facilitated by increased phosphorylation. This in vitro biochemical prototypical may not apply to BRCA2’s cellular action. Structural analysis of BRCA2-Rad51 may shed light on this [46].

BRCA1 is also important for homologous recombination DSB repair, but its mechanism is unclear (Figures 2 and 3). Due to the low stoichiometry of their interaction, it might not directly affect RAD51 function. BRCA1 binds to recombination proteins besides RAD51 [22]. RAD50, MRE11, and NBS1 co-localize and coimmunoprecipitate with BRCA1, but foci localization is unknown. Recent research shows BRCA1 regulates RAD50-MRE11-NBS1. MRE11’s exonuclease may repair DSBs [47]. How this process aids DNA repair is unknown. The BRCA1-complex interaction indicates proximal roles.

Figure 3.

Functional features of BRCA proteins. The BRCA protein has many activities in diverse biological processes including DNA repair, transcription regulation, cell cycle progression, ubiquitination cycle, and chromatin structure regulation. Proteins that are interconnecting with RAD50 double-strand break repair protein (RAD50), Nijmegen breakage syndrome (NBS), meiotic recombination homolog a (MRE1), RAD51 double-strand break repair protein (RAD51), master regulator of cellular metabolism and proliferation (C-Myc), estrogen receptor (ER), tumor protein (P53), mothers against decapentaplegic homolog 3 (Smad3), histone deacetylases (HDAC), retinoblastoma protein (RB), BRCA1 associated Ring domain 1 (BARD1), ubiquitin-like, PHD, and RING finger domain 1 (UHRF1), checkpoint kinase 1 (CHK1), cyclin-dependent kinase inhibitor 1 (CIP1), mediator of DNA damage checkpoint 1 (MDC1) in numerous cellular pathways.

6.2 BRCA gene-dependent transcriptional regulation

There is evidence from numerous studies indicating the transcriptional control of genes is regulated by both the BRCA1 and BRCA2 proteins [48]. The DNA plasmid that contained a BRCA1 C-terminal fragment (aa1528–1863) coupled to the yeast GAL4 (galactose–responsive transcription factor) DNA–binding dominion was used in the first investigations that revealed a role for BRCA1 in transcriptional regulation (GAL4-BRCA1). In both human and yeast cells, this recombinant protein triggered the transcription of genes. The prevalence of BRCA1 mutations in patients with breast and ovarian cancer dramatically decreased this transcriptional activity [49].

Despite the fact that the BRCA1 protein includes a DNA binding domain, recent research has shown that it is a co-regulator rather than a sequence-specific transcriptional component. Numerous transcriptional regulators, such as OCT-1, c-Myc, ER, p53, Smad3, and others, are controlled by BRCA1 [50]. For instance, BRCA1 interaction with ER controls VEGF transcription in breast cancer. It has been demonstrated that the C-terminal region of BRCA1 stimulates the p53 target gene MDM2 (Mouse Double Minute 2 Homolog) in breast cancer cells. It has been proven that BRCA1 and Smad3 work together to induce the Smad3-specific promoter. Various scientific investigations have linked BRCA2 to the control of transcription, for instance via forming a composite with p53 and Smad3 [51].

6.3 Role of BRCA gene in cell cycle progression and regulation

BRCA1 is discovered to be hyperphosphorylated in later G1 and S phases of the cell cycle and dephosphorylated in the M phase, indicating that it governs cell cycle progression, according to early research [52]. At DNA damage detectors, ATM, ATR, and Chk1 phosphorylate BRCA1 when there is DNA damage [53]. BRCA1 hinders G1/S by activating p21WAF1/CIP1. In addition to p21, the BRCA1-induced G1 arrest is dependent on Rb. BRCA1-induced G1/S arrest may be caused by the proteins ATM, ATR, BARD1, RB, p53, and p21 as well as their effectors. BRCA1-deficient cells show genomic instability, centrosome duplication, and DNA damage [54]. Also, BRCA1 acts with a DNA damage checkpoint mediator (MDC1). MDC1 recruits 53BP1, BRCA1, and MRN to DNA break spots to arrest S as well as G2/M cell cycle (Figure 4) [55].

The BRCA2 protein may be involved in the regulation of cell cycle progression, according to a large body of research. BRAF35/BRCA2 complexes on mitotic chromosomes phosphorylate histone H3 at Ser28 and Ser10 to aid in the condensing of mitotic chromosomes. This research verified that BRCA2/BRAF35 is crucial for cell cycle progression by microinjecting anti-BRAF35 or anti-BRCA2 antibodies into HeLa cell nuclei [56]. Recent research has shown that BRCA2-deficient cells are very susceptible to the anti-cancer medication S23906, which is attributable to both a deficiency in HR-dependent DNA repair and a malfunctioning S-phase checkpoint [57].

Figure 4.

The specific role of BRCA1 and BRCA2 in the regulation of the cell cycle. The proteins BRCA1 and BRCA2 and their associated proteins are responsible for cell cycle regulation. ATM and Chk1 phosphorylate BRCA1 at DNA damage detectors. BRCA1 impedes G1/S phase progression by activating TOPBP1 (topoisomerase 2- binding protein 1) and CTIP (C- terminal binding protein 1), induced G2 arrest is also dependent on RAD50 (RAD50 double-strand break repair protein), NBS1 (Nijmegen breakage syndrome 1 mutated gene), and MRE11 (meiotic recombination 11 homolog 1).

6.4 BRCA facilitated chromatin remodeling and regulation of epigenetic gene expression

Genome expression can be controlled by chromatin remodeling, which is regulated by BRCA1. RCA1 and its ubiquitin E3 ligase activities maintain gene silencing. Histone H2A is ubiquitinated to form heterochromatin. Tandemly repeated DNA sequences were produced when BRCA1 was deleted, a pathogenic BRCA1 mutant (T37R) was expressed, or BARD1 shRNA was used [58]. The chromatin remodeling complex SWItch/Sucrose Non-Fermentable (SWI/SNF) contains a BRG1 subunit, which BRCA1 can directly adhere to it. The dominant negative BRG1 mutant blocks p53-mediated BRCA1 transcription. BRCA1-containing chromatin remodeling complexes may lead to breast and ovarian cancer [59]. A novel BRCA1 cofactor (COBRA1) binds directly with endogenous BRCA1 and it can activate chromatin decondensation and is recruited to chromosomes by BRCA1’s BRCT1 domain [60].

Oncogenic microRNAs (miR) have been linked to BRCA1 by several studies. BRCA1-HDAC2 deacetylates H2A, H3, and miR-155. BRCA1 loss and HDAC inhibitors activate MiR-155 and diminish H2A and H3 acetylation, lowering oncomiR expression [61]. High PARP breast cancers upregulate miR-151-5p. This study implies PARP drugs could target miR-151-5p in BRCA1-mutant cancer patients. BRCA1 mutations silence the PEMT gene, which produces choline, a breast tumor nutrition. The PEMT promoter −132’s hypermethylation of the DNA, which raises H3K9me and lowers H3K9ac, is the mechanism underlying this epigenetic repression [62]. BRCA1 regulates sirtuin 1, a NAD-dependent histone deacetylase in cancer. Imbalanced BRCA1 and SIRT1 activity can lead to cellular transformation and tumor growth, and BRCA1 regulates transcription-silencing chromatin modification PRC2. In order for H3K27 tri-methylation, heterochromatin formation, and PRC2 occupancy on chromatin to occur, BRCA1 interacts with the oncogenic lncRNA HOTAIR [63]. These results indicate that BRCA1 inhibits PRC2 to induce breast cancer.

6.5 Degradation of the BRCA proteins via proteasomes and ubiquitination

The cell cycle regulates the post-translational activity of the BRCA1 protein. Also, tumorigenesis ubiquitinates and degrades BRCA2, causing genomic variability and non-familial cancers. Numerous proteins influence the stability of BRCA1/BRCA2, such as the cysteine protease Cathepsin S (CTSS), which binds to the BRCT dominion of BRCA1 and encourages its proteolytic destruction, the E2 ubiquitin-conjugating enzyme E2T (UBE2T), and the E3 ubiquitin ligases Herc2 and F-box protein 44. (FBXO44). BARD1 stabilizes BRCA1 expression [64].

According to Kim et al., Fyn-related kinase (Frk)/Rak positively affects the stability of the BRCA1 protein by directly phosphorylating BRCA1 [61]. BRCA2 3’UTR interacts with miR-19a and miR-19b, lowering mRNA and protein levels. BRCA1/2 is regulated by protein and post-transcriptional control [65]. Chronic myeloid leukemia cells with BCR-ABL1 have less BRCA1. By attaching to 3’UTR ARE sites, the TIRA (TIA1 cytotoxic granule-associated RNA-binding protein-like1) protein prevents BRCA1 mRNA translation. HuR mRNA-binding protein improved mRNA stability and translation in the same research [66]. BRCA1 is silenced by UHRF1 (ubiquitin-like, PHD, and RING finger domain 1). By building up repressive histone marks on the promoter and restricting transcription factor binding, UHRF1 controls the transcription of BRCA1 [67].

6.6 BRCA protein function in autophagy

BRCA1 and BRCA2 are both necessary for quality control, the autophagy route for damaged mitochondria, and mitophagy. After being given oligomycin, antimycin A, or the PARP inhibitor AZD2281, mitophagy was reduced when BRCA1 and BRCA2 were knocked down. Under ER stress and serum fasting, siRNA-mediated BRCA1 knockdown induced pro-survival autophagy. BRCA1 activation triggers protective autophagy. Chemotherapeutic drugs enhanced pro-survival autophagy in BRCA1-mutated ovarian cells [68]. This study revealed that BRCA1 modulates chemotherapy-induced tumor cell death.

6.7 Classical or novel BRCA1 cytoplasmic functions

BRCA1 is widely recognized as a nucleoplasmic chromosomal caretaker. Several studies reveal BRCA1’s cytoplasmic function. BRCA1 is recognized for regulating centrosomes. Centrosome amplification (CA) is common in human malignancies. CA can cause cancer and a poor prognosis [69]. BRCA1 ubiquitinates -tubulin in late S and G2/M via the BRCA1–BARD1–OLA1 complex. BRCA1 reduces early S-phase centrosome microtubule nucleation [70]. According to these results, loss of BRCA1 centrosome control may promote hypertrophy and aneuploidy in breast cancers. Cytoplasm BRCA1 is also implicated in apoptosis. BRCA1 promotes GADD45-independent apoptosis. BARD1 masks BRCA1’s nuclear export signal and retains it in the nucleus. Nuclear export and cytoplasmic accumulation induce apoptosis with BRCA1 overexpression [71].

7. The consequences of the BRCA gene

When BRCA gene phenotypes are identified in malignancies, it may be possible to develop cytotoxic agent regimens that are targeted at the mechanisms that cause DNA-repair abnormalities in cancer cells. BRCA2 and other FA (Fanconi anemia) gene dysfunction cause cells to be extremely sensitive to cancer treatment that cause DNA crosslinks [72]. In contrast, Tumor cells with BRCA1 mutations are sensitive to DNA-crosslinking agents, but susceptible to mitotic-spindle poisons like taxanes [73]. Because taxanes are widely used in the treatment of breast and ovarian cancer, it’s going to be essential for researchers to ascertain in clinical trials which of these tumors are resistant to taxanes. A study will randomize patients with metastatic familial-BRCA1/2 breast tumors among docetaxel and carboplatin treatment to test whether in vitro investigations translate into better clinical efficacy [74]. If employed successfully, similar techniques might be utilized to treat tumors that have the BRCA gene.

8. Concluding remarks and perspectives

The BRCA1 and BRCA2 genes encrypt proteins whose main task is to act as tumor suppressors and play a significant role in genome stability. These two genes contribute to DNA damage pathways, cell cycle, and apoptotic cascades in hereditary breast cancer. Despite changes in sequence and structure, BRCA1 and BRCA2 proteins have similar biological roles. Both BRCA gene products interact with RAD51, an important DNA-repair protein. Defective BRCA gene products impair their function as tumor suppressors, resulting in an elevated risk of cancer. An extensive study shows that BRCA1/2 gene mutations lead to the progress of breast, ovarian, and prostate cancers. BRCA-mutated malignancies are more susceptible to treatments that produce DNA DSBs, such as platinum-based drugs and PARP inhibitors. Reverting BRCA mutations that reinstate BRCA1/2 protein function is a solely clinical challenge that necessitates the careful analysis of restored gene frequencies during treatment. Notably, BRCA reversion mutations during antitumor therapy show that BRCA deficiency is crucial during oncogenesis. Combining other cancer-related therapies, CSC (cancer stem cells) therapy, and immunotherapy could resolve BRCA reversion resistance and enhance therapeutic effectiveness. Novel activities will result from the discovery of numerous additional BRCA protein binding proteins in the future. BRCA proteins’ involvement in epithelial cell biology and transformation is as yet unclear.

Conflict of interest

The authors declare no conflicts of interest.