BRCA1 in cancer, cell cycle and genomic stability
BRCA1 in cancer, cell cycle and genomic stability
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DOI：
10.2741/1131
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发表时间：
2003-09-01
影响因子：
3.1
通讯作者：
Jhanwar-Uniyal, M
中科院分区：
文献类型：
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作者：
Jhanwar-Uniyal, M
BRCA 1基因在1994年被分离出来;已知该基因的生殖系突变会使高危家族易患乳腺癌和卵巢癌。自发现以来，已在该基因中鉴定出几种突变;这些突变分散在整个基因中，包括插入和缺失移码、碱基取代和推断的调控突变。它在乳腺癌发病机制中的作用，占近95%，尽管迄今尚未证实，但不能排除。散发性肿瘤细胞中该基因的两个拷贝的功能失活并不遵循传统模式：BRCA 1功能的丧失并不伴随着肿瘤细胞中该基因的潜在突变以及BRCA 1基因杂合性的丧失。现在有几项研究表明，一种替代的失活机制，涉及启动子超甲基化，导致基因表达减少，可能是一个显着比例的散发性乳腺癌和卵巢癌的共同点。BRCA 1作为一种肿瘤抑制因子，在维持基因组稳定性方面发挥着重要作用。BRCA 1能够与许多蛋白质相互作用，并形成参与识别和随后修复DNA的复合物。BRCA 1含有几个功能结构域，通过蛋白质-蛋白质相互作用与多种蛋白质直接或间接相互作用;包括肿瘤抑制剂（BRCA 2、p53、Rb和ATM），癌基因（c-Myc，酪蛋白激酶II和E2 F），DNA损伤修复蛋白（RAD 50和RAD 51），细胞周期调节剂（细胞周期蛋白和细胞周期蛋白依赖性激酶），转录激活因子和抑制因子（RNA聚合酶II、RHA、组蛋白脱乙酰酶复合物和CtIP）、DNA损伤感应复合物和错配修复蛋白（BRCA 1-相关监测综合体; BASC）和信号转导和转录激活因子（STAT）等通过遗传突变或表观遗传机制形成含有BRCA 1的病灶在散发性癌症中的启动子甲基化导致DNA修复能力的丧失，破坏了与其他蛋白质形成复合物的潜力，这些蛋白质对DNA修复途径至关重要。因此，BRCA 1在维持基因组稳定性方面起着重要作用，并在乳腺癌肿瘤发生中充当肿瘤抑制因子。
The BRCA1 gene was isolated in 1994; germline mutations of this gene are known to confer susceptibility to breast and ovarian cancer in high-risk families. Since its discovery, several mutations have been identified in this gene; these are scattered throughout the gene, and include insertion and deletion frameshifts, base substitutions, and inferred regulatory mutations. It role in the pathogenesis of breast cancer, which accounts for almost 95%, although unproven to date, cannot be ruled out. The functional inactivation of both copies of this gene in sporadic tumor cells does not follow the traditional mode: the loss of function in BRCA1 is not accompanied by underlying mutation of the gene in tumor cells with loss of heterozygosity for the BRCA1 gene. Several studies now suggest that an alternate mechanism of inactivation, involving promoter hypermethylation that results in reduced expression of the gene, may be common to a significant proportion of sporadic breast and ovarian cancers. BRCA1 as a tumor suppressor plays an important role in maintaining genomic stability. BRCA1 has the ability to interact with numerous proteins and to form complexes that are involved in recognizing and subsequently repairing DNA. BRCA1 contains several functional domains that directly or indirectly interact with a variety of proteins via protein-protein interaction; these include tumor suppressors (BRCA2, p53, Rb and ATM), oncogenes (c-Myc, casein kinase II and E2F), DNA damage repair proteins (RAD50 and RAD51), cell cycle regulators (cyclins and cyclin dependent kinases), transcriptional activators and repressors (RNA polymerase II, RHA, histone deacetylase complex and CtIP), DNA damage-sensing complex and mismatch repair proteins (BRCA1-Associated Surveillance Complex; BASC) and signal transducer and activator of transcription (STAT) among others Formation of foci containing BRCA1 by inherited mutations, or epigenetic mechanisms (promoter methylation) in sporadic cancers leads to a loss of DNA repair ability, disrupts the potential to form complexes with other proteins that are crucial for DNA repair pathways. Thus, BRCA1 plays a significant role in maintaining genomic stability and serves as a tumor suppressor in breast cancer tumorigenesis.