| BRCA1 DNA repair associated | OKDB#: 14 |
| Symbols: | BRCA1 | Species: | human | ||
| Synonyms: | IRIS, PSCP, BRCAI, BRCC1, FANCS, PNCA4, RNF53, BROVCA1, PPP1R53 | Locus: | 17q21.31 in Homo sapiens |
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| General Comment |
The breast tumor suppressor gene BRCA1 was identified by positional cloning methods (Miki et al., 1994). Mutations of this gene also lead to ovarian cancer in some families. BRCA1 encodes a zinc finger, DNA binding protein.
NCBI Summary: This gene encodes a nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2009] |
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| General function | Cell death/survival, Cell cycle regulation, Tumor suppressor | ||||
| Comment | BRCA1, and BRCA2, may participate together in a pathway associated with the activation of double-strand break repair and/or homologous recombination. //////////BRCA1 germline mutations may be associated with reduced ovarian reserve. Wang ET 2014 et al. OBJECTIVE To determine whether BRCA carriers have a decreased ovarian reserve compared with women without BRCA mutations, because BRCA mutations may lead to accelerated oocyte apoptosis due to accumulation of damaged DNA. DESIGN Cross-sectional study. SETTING Academic tertiary care center. PATIENT(S) A total of 143 women, aged 18-45years, who underwent clinical genetic testing for BRCA deleterious mutations because of a family history of cancer, were included. The cohort was classified into three groups: BRCA1 carriers, BRCA2 carriers, and women without BRCA mutations (controls). None had a personal history of breast or ovarian cancer. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) The main outcome was serum anti-Mllerian hormone (AMH) level. Linear and logistic regression models adjusting for age and body mass index (BMI) were performed to determine the association between BRCA mutations and AMH. RESULT(S) BRCA1 mutation carriers had a significant decrease in AMH levels compared with controls after adjusting for age and BMI (0.53ng/mL [95% confidence interval (CI) 0.33-0.77ng/mL] vs. 1.05ng/mL [95% CI 0.76-1.40ng/mL]). Logistic regression confirmed that BRCA1 carriers had a fourfold greater odds of having AMH <1ng/mL compared with controls (odds ratio 4.22, 95% CI 1.48-12.0). There was no difference in AMH levels between BRCA2 carriers and controls. CONCLUSION(S) BRCA1 carriers have lower age- and BMI-adjusted serum AMH levels compared with women without BRCA mutations. Our results contribute to the current body of literature regarding BRCA carriers and their reproductive outcomes. Larger prospective studies with clinical outcomes such as infertility and age at menopause in this population are needed to further substantiate our findings. ///////////////////////// | ||||
| Cellular localization | Nuclear | ||||
| Comment | BRCA Mutations, DNA Repair Deficiency and Ovarian Aging. Oktay K et al. (2015) Oocyte aging has a significant impact on reproductive outcomes both quantitatively and qualitatively. However, the molecular mechanisms underlying the age-related decline in reproductive success have not been fully addressed. BRCA is known to be involved in homologous DNA recombination and plays an essential role in double-strand DNA break (DSB) repair. Given the growing body of laboratory and clinical evidence, we performed a systematic review on the current understanding of the role of DNA repair in human reproduction. We find that BRCA mutations negatively affect ovarian reserve based on convincing evidence from in vitro and in vivo data and prospective studies. Because the decline in the function of the intact gene occurs at an earlier age, women with BRCA1 mutations exhibit accelerated ovarian aging unlike those with BRCA2 mutations. However, because of the still robust function of the intact allele in younger women and due to masking of most severe cases by prophylactic oophorectomy or cancer, it is less likely to see an effect of BRCA mutations on fertility until later in reproductive age. The impact of BRCA2 mutations on reproductive function may be less visible because of the delayed decline in the function of the normal BRCA2 allele. BRCA1 function and ATM-mediated DNA repair may also be important in the pathogenesis of age-induced increase in aneuploidy. BRCA1 is required for meiotic spindle assembly, and cohesion function between sister-chromatids is also regulated by ATM-family member proteins. Taken together, these findings strongly suggest the implication of BRCA and DNA repair malfunction in ovarian aging.////////////////// | ||||
| Ovarian function | Oocyte maturation | ||||
| Comment | BRCA mutation carriers show normal ovarian response in in vitro fertilization cycles. Shapira M et al. (2015) To evaluate the association between carriage of BRCA1/2 mutations and ovarian performance, as demonstrated by in vitro fertilization (IVF) outcomes. Retrospective cohort study. Two tertiary IVF centers. BRCA mutation carriers undergoing IVF for preimplantation genetic diagnosis (PGD) or fertility preservation were compared with non-BRCA PGD or fertility preservation patients, matched by age, IVF protocol, IVF center, and cancer disease status. In vitro fertilization cycles for PGD and fertility preservation. Outcome of IVF: oocyte yield, poor response rate, number of zygotes, pregnancy rates. A total of 62 BRCA mutation carriers and 62 matched noncarriers were included; 42 were fertility preservation breast cancer patients, and 82 were PGD non-cancer patients. Mean (±SD) age of patients was 32 ± 3.58 years. Number of stimulation days and total stimulation dose were comparable between carriers and noncarriers. Their cycles resulted in comparable oocyte yield (13.75 vs. 14.75) and low response rates (8.06% vs. 6.45%). Number of zygotes, fertilization rates, and conception rates were also comparable. Both healthy and cancer-affected BRCA mutation carriers demonstrated normal ovarian response in IVF cycles.////////////////// BRCA1 Is Required for Meiotic Spindle Assembly and Spindle Assembly Checkpoint Activation in Mouse Oocytes. Xiong B et al. BRCA1, as a tumor suppressor, has been widely investigated in mitosis, but its functions in meiosis are unclear. In the present study, we examined the expression, localization and function of BRCA1 during mouse oocyte meiotic maturation. We found that expression level of BRCA1 was increased progressively from GV to MI stage, and then remained stable till MII stage. Immunofluorescent analysis showed that BRCA1 was localized to the spindle poles at metaphase I and metaphase II stages, colocolizing with centrosomal protein gamma-tubulin. Taxol treatment resulted in the presence of BRCA1 onto the spindle microtubule fibers, while nocodazole treatment induced the localization of BRCA1 onto the chromosomes. Depletion of BRCA1 by both antibody injection and siRNA injection caused severely impaired spindles as well as misaligned chromosomes. Furthermore, BRCA1-depleted oocytes could not arrest at the metaphase I in the presence of low-dose nocodazole, suggesting that the spindle checkpoint is defective. Also, in BRCA1-depleted oocytes, gamma-tubulin dissociated from spindle poles and MAD2L1 failed to rebind to the kinetochores when exposed to nocodazole at metaphase I stage. Collectively, these data indicate that BRCA1 regulates not only meiotic spindle assembly, but also spindle assembly checkpoint, implying a link between BRCA1 deficiency and aneuploid embryos. | ||||
| Expression regulated by | |||||
| Comment | Brca1 expression in the mouse ovary occurs independently of hormonal status and in the absence of a major estrogen receptor-mediated pathway; it is, however, closely correlated with cell cycle in mouse ovarian granulosa, thecal, and luteal cell (Phillips et al., 1997). | ||||
| Ovarian localization | Oocyte, Cumulus, Granulosa, Theca, Luteal cells, Surface epithelium | ||||
| Comment | Brca1 was consistently expressed in granulosa and thecal cells of follicle populations that proliferate independently of hormonal stimulation. Brca1 expression was also localized to luteal cells of recently formed corpora lutea and corpora lutea associated with pregnancy (Phillips et al.,1997). In the cynomolgus monkey strong BRCA1 expression was detected in granulosa cells in maturing follicles and in luteal cells of the corpus luteum, as well as in the epithelial cells overlying the tunica albuginea (Durocher et al., 1997). | ||||
| Follicle stages | Secondary, Antral, Corpus luteum | ||||
| Comment | Increased DNA damage and repair deficiency in granulosa cells are associated with ovarian aging in rhesus monkey. Zhang D et al. (2015) Ovarian aging is closely tied to the decline in ovarian follicular reserve and oocyte quality. During the prolonged reproductive lifespan of the female, granulosa cells connected with oocytes play critical roles in maintaining follicle reservoir, oocyte growth and follicular development. We tested whether double-strand breaks (DSBs) and repair in granulosa cells within the follicular reservoir are associated with ovarian aging. Ovaries were sectioned and processed for epi-fluorescence microscopy, confocal microscopy, and immunohistochemistry. DNA damage was revealed by immunstaining of γH2AX foci and telomere damage by γH2AX foci co-localized with telomere associated protein TRF2. DNA repair was indicated by BRCA1 immunofluorescence. DSBs in granulosa cells increase and DSB repair ability, characterized by BRCA1 foci, decreases with advancing age. γH2AX foci increase in primordial, primary and secondary follicles with advancing age. Likewise, telomere damage increases with advancing age. In contrast, BRCA1 foci in granulosa cells of primordial, primary and secondary follicles decrease with monkey age. BRCA1 positive foci in the oocyte nuclei also decline with maternal age. Increased DSBs and reduced DNA repair in granulosa cells may contribute to ovarian aging. Discovery of therapeutics that targets these pathways might help maintain follicle reserve and postpone ovarian dysfunction with age.////////////////// Ubiquitination and Proteasome-Mediated Degradation of BRCA1 and BARD1 During Steroidogensis in Human Ovarian Granulosa Cells Lu Y, et al . Germ-line mutations in BRCA1 predispose women to early onset, familial breast and ovarian cancers. However, BRCA1 expression is not restricted to breast and ovarian epithelial cells. For example, ovarian BRCA1 expression is enriched in ovarian granulosa cells, which are responsible for ovarian estrogen production in premenopausal women. Furthermore, recent tissue culture and animal studies suggest a functional role of BRCA1 in ovarian granulosa cells. While levels of BRCA1 are known to fluctuate significantly during folliculogenesis and steroidogensis, the mechanism by which BRCA1 expression is regulated in granulosa cells remains to be elucidated. Here we show that the ubiquitin-proteasome degradation pathway plays a significant role in the coordinated protein stability of BRCA1 and its partner BARD1 in ovarian granulosa cells. Our work identifies the amino-terminal RING domain-containing region of BRCA1 as the degron sequence that is both necessary and sufficient for polyubiquitination and proteasome-mediated protein degradation. Interestingly, mutations in the RING domain that abolish the ubiquitin E3 ligase activity of BRCA1 do not affect its own ubiquitination or degradation in ovarian granulosa cells. The proteasome-mediated degradation of BRCA1 and BARD1 also occurs during the cAMP-dependent steroidogenic process. Thus, the dynamic changes of BRCA1/BARD1 protein stability in ovarian granulosa cells provide an excellent paradigm for investigating the regulation of this protein complex under physiological conditions. | ||||
| Phenotypes |
POF (premature ovarian failure) |
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| Mutations |
6 mutations
Species: mouse
Species: human
Species: human
Species: human
Species: mouse
Species: mouse
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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| created: | March 10, 1999, midnight | by: |
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| last update: | March 21, 2020, 12:13 p.m. | by: | hsueh email: |
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