Basic Biomedical Science Division, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA.
Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13558-63. doi: 10.1073/pnas.1306534110. Epub 2013 Jul 30.
Breast cancer gene 1 (BRCA1) deficient cells not only are hypersensitive to double-strand breaks but also are hypersensitive to UV irradiation and other agents that cause replication blockade; however, the molecular mechanisms behind these latter sensitivities are largely unknown. Here, we report that BRCA1 promotes cell survival by directly regulating the DNA damage tolerance pathway in response to agents that create cross-links in DNA. We show that BRCA1 not only promotes efficient mono- and polyubiquitination of proliferating cell nuclear antigen (PCNA) by regulating the recruitment of replication protein A, Rad18, and helicase-like transcription factor to chromatin but also directly recruits translesion polymerases, such as Polymerase eta and Rev1, to the lesions through protein-protein interactions. Our data suggest that BRCA1 plays a critical role in promoting translesion DNA synthesis as well as DNA template switching.
乳腺癌基因 1（BRCA1）缺陷细胞不仅对双链断裂高度敏感，而且对紫外线照射和其他导致复制阻滞的试剂也高度敏感；然而，这些后者敏感性的分子机制在很大程度上是未知的。在这里，我们报告 BRCA1 通过直接调节 DNA 损伤耐受途径来促进细胞存活，以响应在 DNA 中产生交联的试剂。我们表明 BRCA1 不仅通过调节复制蛋白 A、Rad18 和螺旋酶样转录因子向染色质的募集来促进增殖细胞核抗原（PCNA）的有效单泛素化和多泛素化，而且还通过蛋白-蛋白相互作用直接将跨损伤聚合酶，如聚合酶 eta 和 Rev1，募集到损伤部位。我们的数据表明 BRCA1 在促进跨损伤 DNA 合成以及 DNA 模板转换方面发挥着关键作用。
