Telomere and Genome Stability Group, The Cancer Research UK/Medical Research Council Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford, UK.
Nat Struct Mol Biol. 2010 Dec;17(12):1461-9. doi: 10.1038/nsmb.1943. Epub 2010 Nov 14.
The tumor suppressor protein BRCA2 is a key component of the homologous recombination pathway of DNA repair, acting as the loader of RAD51 recombinase at sites of double-strand breaks. Here we show that BRCA2 associates with telomeres during the S and G2 phases of the cell cycle and facilitates the loading of RAD51 onto telomeres. Conditional deletion of Brca2 and inhibition of Rad51 in mouse embryonic fibroblasts (MEFs), but not inactivation of Brca1, led to shortening of telomeres and accumulation of fragmented telomeric signals--a hallmark of telomere fragility that is associated with replication defects. These findings suggest that BRCA2-mediated homologous recombination reactions contribute to the maintenance of telomere length by facilitating telomere replication and imply that BRCA2 has an essential role in maintaining telomere integrity during unchallenged cell proliferation. Mouse mammary tumors that lacked Brca2 accumulated telomere dysfunction-induced foci. Human breast tumors in which BRCA2 was mutated had shorter telomeres than those in which BRCA1 was mutated, suggesting that the genomic instability in BRCA2-deficient tumors was due in part to telomere dysfunction.
肿瘤抑制蛋白 BRCA2 是 DNA 修复同源重组途径的关键组成部分，作为 RAD51 重组酶在双链断裂部位的加载器。在这里，我们表明 BRCA2 在细胞周期的 S 和 G2 期与端粒结合，并促进 RAD51 加载到端粒上。在小鼠胚胎成纤维细胞（MEFs）中条件性删除 Brca2 和抑制 Rad51，但不使 Brca1 失活，导致端粒缩短和碎片化端粒信号的积累——这是与复制缺陷相关的端粒脆弱性的标志。这些发现表明，BRCA2 介导的同源重组反应通过促进端粒复制有助于维持端粒长度，并暗示 BRCA2 在未受挑战的细胞增殖过程中端粒完整性的维持中起着至关重要的作用。缺乏 Brca2 的小鼠乳腺肿瘤积累了端粒功能障碍诱导的焦点。与 BRCA1 突变的人类乳腺癌相比，BRCA2 突变的肿瘤具有更短的端粒，这表明 BRCA2 缺陷型肿瘤中的基因组不稳定性部分归因于端粒功能障碍。
