CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair
CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair
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DOI：
10.1038/nature03404
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发表时间：
2005-03-31
期刊：
影响因子：
64.8
通讯作者：
West, SC
中科院分区：
文献类型：
--
作者：
Esashi, F;Christ, N;West, SC
BRCA2的遗传突变与早发性乳腺癌的易感性有关。肿瘤发生的潜在基础被认为与DNA双链断裂修复的同源重组缺陷有关。在这里，我们发现BRCA2的羧基末端区域，直接与必需的重组蛋白RAD51相互作用，包含一个位点（丝氨酸3291；S3291），该位点被周期蛋白依赖性激酶磷酸化。当重组活跃时，S3291的磷酸化在S期较低，但随着细胞向有丝分裂的进展而增加。这种修饰阻断了BRCA2和RAD51之间的c端相互作用。然而，DNA损伤通过降低S3291磷酸化和刺激与RAD51的相互作用来克服细胞周期调节。这些结果表明，S3291磷酸化可能提供了调节RAD51重组活性的分子开关，为BRCA2 c端缺失导致辐射敏感性和癌症易感性的原因提供了新的见解。
Inherited mutations in BRCA2 are associated with a predisposition to early-onset breast cancers. The underlying basis of tumorigenesis is thought to be linked to defects in DNA double-strand break repair by homologous recombination. Here we show that the carboxy-terminal region of BRCA2, which interacts directly with the essential recombination protein RAD51, contains a site (serine 3291; S3291) that is phosphorylated by cyclin-dependent kinases. Phosphorylation of S3291 is low in S phase when recombination is active, but increases as cells progress towards mitosis. This modification blocks C-terminal interactions between BRCA2 and RAD51. However, DNA damage overcomes cell cycle regulation by decreasing S3291 phosphorylation and stimulating interactions with RAD51. These results indicate that S3291 phosphorylation might provide a molecular switch to regulate RAD51 recombination activity, providing new insight into why BRCA2 C-terminal deletions lead to radiation sensitivity and cancer predisposition.