The Medical Research Council (MRC) Cancer Unit, University of Cambridge, Hutchison-MRC Research Centre, Cambridge, UK.
Nat Struct Mol Biol. 2013 Oct;20(10):1191-8. doi: 10.1038/nsmb.2666. Epub 2013 Sep 8.
Germline missense mutations affecting a single BRCA2 allele predispose humans to cancer. Here we identify a protein-targeting mechanism that is disrupted by the cancer-associated mutation, BRCA2(D2723H), and that controls the nuclear localization of BRCA2 and its cargo, the recombination enzyme RAD51. A nuclear export signal (NES) in BRCA2 is masked by its interaction with a partner protein, DSS1, such that point mutations impairing BRCA2-DSS1 binding render BRCA2 cytoplasmic. In turn, cytoplasmic mislocalization of mutant BRCA2 inhibits the nuclear retention of RAD51 by exposing a similar NES in RAD51 that is usually obscured by the BRCA2-RAD51 interaction. Thus, a series of NES-masking interactions localizes BRCA2 and RAD51 in the nucleus. Notably, BRCA2(D2723H) decreases RAD51 nuclear retention even when wild-type BRCA2 is also present. Our findings suggest a mechanism for the regulation of the nucleocytoplasmic distribution of BRCA2 and RAD51 and its impairment by a heterozygous disease-associated mutation.
胚系错义突变影响单个 BRCA2 等位基因使人类易患癌症。在这里，我们确定了一种蛋白质靶向机制，该机制被癌症相关突变 BRCA2(D2723H)破坏，并控制 BRCA2 及其货物重组酶 RAD51 的核定位。BRCA2 中的核输出信号 (NES) 被其与伴侣蛋白 DSS1 的相互作用所掩盖，使得破坏 BRCA2-DSS1 结合的点突变使 BRCA2 细胞质化。反过来，突变型 BRCA2 的细胞质定位错误通过暴露出 RAD51 中的类似 NES 来抑制 RAD51 的核保留，该 NES 通常被 BRCA2-RAD51 相互作用掩盖。因此，一系列 NES 掩蔽相互作用将 BRCA2 和 RAD51 定位在核内。值得注意的是，即使存在野生型 BRCA2，BRCA2(D2723H)也会降低 RAD51 的核保留。我们的发现为 BRCA2 和 RAD51 的核质分布的调节及其由杂合疾病相关突变破坏的机制提供了依据。
