RIF1 Counteracts BRCA1-mediated End Resection during DNA Repair
RIF1 Counteracts BRCA1-mediated End Resection during DNA Repair
复制标题
DOI：
10.1074/jbc.m113.457440
复制
发表时间：
2013-04-19
影响因子：
4.8
通讯作者：
Chen, Junjie
中科院分区：
文献类型：
--
作者：
Feng, Lin;Fong, Ka-Wing;Chen, Junjie
BRCA1 促进同源重组修复并拮抗 53BP1 依赖性非同源末端连接 (NHEJ) 途径。然而，BRCA1 和 53BP1 通路之间竞争的分子基础仍然难以捉摸。在此，我们报告 RIF1 蛋白通过 ATM 依赖性 53BP1 磷酸化易位至损伤位点。引人注目的是，RIF1 的缺失挽救了 BRCA1 耗尽细胞中最初的 DNA 末端切除和检查点激活。有趣的是，RIF1 在损伤部位的积累被 S 期和 G(2) 期的 BRCA1 拮抗。相反，BRCA1 向损伤位点的易位被 G(1) 期的 RIF1 抑制。然而，RIF1 的缺失与 53BP1 缺陷不同，因为它不能完全挽救 BRCA1 缺陷细胞中的 RAD51 灶形成、同源重组缺陷和放射过敏。这可能是因为 RIF1（而非 53BP1）也调节 BLM（布卢姆综合征解旋酶）的病灶形成和染色质负载。因此，RIF1 不仅作用于 53BP1 下游并抵消 BRCA1 介导的末端切除，而且在促进 DNA 修复中的 BLM 功能方面也具有次要作用。
BRCA1 promotes homologous recombination repair and antagonizes 53BP1-dependent nonhomologous end joining (NHEJ) pathway. However, the molecular basis of the competition between BRCA1 and 53BP1 pathways remains elusive. Here we report that RIF1 protein translocates to damage sites via ATM-dependent 53BP1 phosphorylation. Strikingly, loss of RIF1 rescues initial DNA end resection and checkpoint activation in BRCA1-depleted cells. Interestingly RIF1 accumulation at damage sites is antagonized by BRCA1 in S and G(2) phases. Conversely, the translocation of BRCA1 to damage sites is inhibited by RIF1 in G(1) phase. However, loss of RIF1 differs from that of 53BP1 deficiency, as it cannot fully rescue RAD51 foci formation, homologous recombination defect, and radio-hypersensitivity in BRCA1-deficient cells. This is likely because RIF1, but not 53BP1, also regulates the foci formation and chromatin loading of BLM (the Bloom syndrome helicase). Thus, RIF1 not only acts downstream of 53BP1 and counteracts BRCA1-mediated end resection but also has a secondary role in promoting BLM function in DNA repair.