BRCA1
小结
BRCA1是抑癌基因，作为多功能泛素连接酶E3起作用。 BRCA1涉及调节多种细胞过程，包括转录，蛋白质泛素化，细胞周期调节和DNA损伤反应；在同源重组过程中的DNA修复中具有特别重要的作用。BRCA1常与已知的肿瘤抑制因子形成蛋白质复合物发挥作用，包括RAD51，BRCA2，BARD1和PALB2；具体地，BRCA1和BARD1促进DNA末端的切除并增强重组酶RAD51的活性。BRCA1是第一个鉴定和克隆的乳腺癌和卵巢癌易感基因，该基因胚系致病突变导致患乳腺癌和卵巢癌的终生风险增加，BRCA1胚系致病突变可导致乳腺癌的终生风险可达到70-80%。BRCA1胚系杂合致病突变可导致遗传性乳腺-卵巢综合征，因为该综合征是常染色体显性遗传病。同时，BRCA1也时Fanconi贫血易感基因，需要BRCA1发生双等位基因突变才会患病，因为Fanconi贫血属于一种常染色体隐形遗传病。在乳腺癌肿瘤中，TP53突变几乎全部和BRCA1和BRCA2同时突变，表明TP53功能丧失可能是BRCA相关肿瘤发生的必要步骤。
BBRCA1 (breast cancer susceptibility gene 1) is a tumor suppressor gene that functions as a multifunctional ubiquitin E3 ligase. BRCA1 has been implicated in regulating diverse cellular processes including transcription, protein ubiquitination, cell cycle regulation and DNA damage response, with a particularly important role in DNA repair during homologous recombination. BRCA1 forms protein complexes with known tumor suppressors including RAD51, BRCA2, BARD1 and PALB2; specifically, BRCA1 and BARD1 facilitate resection of DNA ends and enhance the activity of the recombinase RAD51 . BRCA1 was the first breast and ovarian cancer susceptibility gene identified and cloned; inherited mutations in this gene lead to an increased lifetime risk of developing these cancers. BRCA1 mutations confer a 70-80% lifetime risk of breast cancer, a 50% lifetime risk of ovarian cancer and an increased risk of prostate cancer in patients with Ashkenazi Jewish BRCA1 founder mutations. If one copy of BRCA1 is mutated in the germline, the result is hereditary breast and ovarian cancer (HBOC) syndrome, an autosomal dominant disease. BRCA1 was also recently identified as a definitive Fanconi anemia susceptibility gene in FANCS, a rare Fanconi anemia subtype that results from biallelic mutations in the gene. BRCA1 mutations are predicted to disrupt protein-protein interactions, which facilitate DNA repair. Mutations in TP53 in breast tumors are seen almost exclusively with BRCA1 and BRCA2 mutations, suggesting that TP53 loss of function may be a necessary step in the tumorigenesis of BRCA-associated carcinomas. PARP inhibitors are FDA-approved for patients with germline BRCA1-mutant ovarian and breast cancers.