RAD51 up-regulation bypasses BRCA1 function and is a common feature of BRCA1-deficient breast tumors
RAD51 up-regulation bypasses BRCA1 function and is a common feature of BRCA1-deficient breast tumors
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DOI：
10.1158/0008-5472.can-07-0290
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发表时间：
2007-10-15
期刊：
影响因子：
11.2
通讯作者：
Bishop, Douglas K.
中科院分区：
文献类型：
--
作者：
Martin, Richard W.;Orelli, Brian J.;Bishop, Douglas K.
乳腺癌易感基因 BRCA1 编码一种大蛋白，被认为有助于多种细胞过程，但 BRCA1 缺陷肿瘤发生的关键决定因素仍不清楚。鉴于 BRCA1 是细胞增殖所必需的，抑制突变被认为会改变 BRCA1 表型，并导致 BRCA1 缺陷型肿瘤的病因学。在这里，我们证明在 DT40 BRCA1(Delta/Delta) 突变体中同源重组酶 RAD51 的过表达可以挽救增殖、DNA 损伤存活和同源重组 (HR) 方面的缺陷。此外，BRCA1 和 DNA 末端连接因子 KU70 的上位性分析表明，这些因子在修复双链断裂时彼此独立地发挥作用。与这一遗传发现一致，细胞同步研究表明，BRCA1 促进放射抗性的能力仅限于细胞周期的晚期 S 和 G(2) 阶段，正如对功能特定于同源介导的修复而不是非同源末端连接的基因的预测一样。值得注意的是，对微阵列表达数据的回顾性分析显示，与散发性乳腺肿瘤相比，BRCA1 缺陷型乳腺肿瘤中 RAD51 及其两种晚期作用辅助因子 RAD54 和 RAD51AP1 的表达升高。综上所述，我们的结果表明，HR 的上调通过规避 RAD51 胰岛细胞组装中的要求，为缺乏 BRCA1 功能的细胞提供了允许的遗传环境。此外，数据支持这样一个模型：HR 活性增强有助于 BRCA1 缺陷肿瘤的病因学。
The breast cancer susceptibility gene BRCA1 encodes a large protein thought to contribute to a variety of cellular processes, although the critical determinants of BRCA1-deficient tumorigenesis remain unclear. Given that BRCA1 is required for cell proliferation, suppressor mutations are believed to modify BRCA1 phenotypes and contribute to the etiology of BRCA1-deficient tumors. Here, we show that overexpression of the homologous recombinase RAD51 in a DT40 BRCA1(Delta/Delta) mutant rescues defects in proliferation, DNA damage survival, and homologous recombination (HR). In addition, epistasis analysis with BRCA1 and the DNA end-joining factor KU70 indicates that these factors operate independently of one another to repair double-strand breaks. Consistent with this genetic finding, cell synchronization studies show that the ability of BRCA1 to promote radioresistance is restricted to the late S and G(2) phases of the cell cycle, as predicted for genes whose function is specific to homology-mediated repair rather than nonhomologous end-joining. Notably, retrospective analyses of microarray expression data reveal elevated expression of RAD51 and two of its late-acting cofactors, RAD54 and RAD51AP1, in BRCA1-deficient versus sporadic breast tumors. Taken together, our results indicate that upregulation of HR provides a permissive genetic context for cells lacking BRCA1 function by circumventing its requirement in RAD51 sulmuclear assembly. Furthermore, the data support a model in which enhanced HR activity contributes to the etiology of BRCA1-deficient tumors.