Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Nat Struct Mol Biol. 2010 Jun;17(6):688-95. doi: 10.1038/nsmb.1831. Epub 2010 May 9.
Germ-line mutations in breast cancer 1, early onset (BRCA1) result in predisposition to breast and ovarian cancer. BRCA1-mutated tumors show genomic instability, mainly as a consequence of impaired recombinatorial DNA repair. Here we identify p53-binding protein 1 (53BP1) as an essential factor for sustaining the growth arrest induced by Brca1 deletion. Depletion of 53BP1 abrogates the ATM-dependent checkpoint response and G2 cell-cycle arrest triggered by the accumulation of DNA breaks in Brca1-deleted cells. This effect of 53BP1 is specific to BRCA1 function, as 53BP1 depletion did not alleviate proliferation arrest or checkpoint responses in Brca2-deleted cells. Notably, loss of 53BP1 partially restores the homologous-recombination defect of Brca1-deleted cells and reverts their hypersensitivity to DNA-damaging agents. We find reduced 53BP1 expression in subsets of sporadic triple-negative and BRCA-associated breast cancers, indicating the potential clinical implications of our findings.
乳腺癌 1 型，早发（BRCA1）中的种系突变导致乳腺癌和卵巢癌易感性。BRCA1 突变肿瘤表现出基因组不稳定性，主要是由于重组 DNA 修复受损所致。在这里，我们确定 p53 结合蛋白 1（53BP1）是维持 Brca1 缺失诱导的生长停滞所必需的因素。53BP1 的耗竭消除了 ATM 依赖性检查点反应和由 Brca1 缺失细胞中 DNA 断裂积累引发的 G2 细胞周期阻滞。53BP1 的这种作用是 BRCA1 功能特异性的，因为 53BP1 的耗竭不能缓解 Brca2 缺失细胞的增殖停滞或检查点反应。值得注意的是，53BP1 的缺失部分恢复了 Brca1 缺失细胞的同源重组缺陷，并逆转了它们对 DNA 损伤剂的敏感性。我们发现散发性三阴性和 BRCA 相关乳腺癌的亚组中 53BP1 表达降低，表明我们的发现具有潜在的临床意义。
