众所周知，乳腺癌易感基因BRCA1突变后大大增加了乳腺癌和卵巢癌的风险，但相关机制还不完全清楚。现在，美国弗吉尼亚联邦大学梅西癌症中心的研究人员揭示了BRCA1突变导致过度、无节制的DNA修复，这一结论有悖于之前的认识：BRCA1突变仅通过功能丢失有助于引发乳腺癌。
乳腺癌和卵巢癌中遗传基因突变的关键功能被发现
最近发表在《Aging》期刊上，该研究由Kristoffer Valerie 博士领导。他们发现了，BRCA1的特定突变影响C端的结合位点，进而导致了有助于乳腺癌和卵巢癌发生的DNA过度修复或超重组。DNA修复蛋白（如BRCA1）具有蛋白结合位点—BRCT结构域，促进DNA的修复和维持基因组的稳定。
当DNA损伤时，不同形式的BASC（BRCA1相关的基因组侦察复合物）结合在BRCA2上的BRCT结构域。BASC是一种蛋白复合物，其中一部分结合BRCT后为其它蛋白和酶的进入以及有效修复DNA损伤提供了“锚定位点”，当修复完成后，BASC释放掉锚定的蛋白和酶。但是，特定突变的BRCT不能结合在BASC上，因此破坏了DNA修复的精密过程。
在乳腺癌细胞和组织样本的培养实验中，Valerie及同事发现了BRCT突变体增加BASC的泛素化，重组事件也随之增加到正常水平的若干倍。泛素是所用生物体中的一类小分子蛋白质，“标记”待降解的其它蛋白质，并参与近来才发现的特定细胞过程（如重组）。研究人员认为超重组因BASC泛素化水平的提高而引起，导致了不当的DNA修复和基因组稳定性的降低，这些情况很可能引起乳腺癌和卵巢癌的形成和恶化。
Valerie 称，我们的研究表明泛素化是潜在的治疗靶点，通过破坏泛素化，我们可防止超重组以及阻止BRCT突变的肿瘤细胞的生长。
研究人员希望继续研究在DNA双链断裂修复过程中的BRCA1作用，进一步确定突变的BRCA1是否对肿瘤的触发具有重要性以及靶向治疗是否可以形成。（生物探索译 Pobee）
生物探索推荐英文摘要
We introduced a K1702M mutation in the BRCA1 BRCT domain known to prevent the binding of proteins harboring pS-X-X-F motifs such as Abraxas-RAP80, BRIP1, and CtIP. Surprisingly, rather than impairing homologous recombination repair (HRR), expression of K1702M resulted in hyper-recombination coinciding with an accumulation of cells in S-G2 and no effect on nonhomologous end-joining. These cells also showed increased RAD51 and RPA nuclear staining. More pronounced effects were seen with a naturally occurring BRCT mutant (M1775R) that also produced elevated levels of ssDNA, in part co-localizing with RPA, in line with excessive DNA resection. M1775R induced unusual, thread-like promyelocytic leukemia (PML) nuclear bodies and clustered RPA foci rather than the typical juxtaposed RPA-PML foci seen with wild-type BRCA1. Interestingly, K1702M hyper-recombination diminished with a second mutation in the BRCA1 RING domain (I26A) known to reduce BRCA1 ubiquitin-ligase activity. Thesein vitro findings correlated with elevated nuclear RAD51 and RPA staining of breast cancer tissue from a patient with the M1775R mutation. Altogether, the disruption of BRCA1 (BRCT)-pS-X-X-F protein binding results in ubiquitination-dependent hyper-recombination via excessive DNA resection and the appearance of atypical PML-NBs. Thus, certain BRCA1 mutations that cause hyper-recombination instead of reduced DSB repair might lead to breast cancer.
