Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160, USA.
J Biol Chem. 2011 Apr 15;286(15):13669-80. doi: 10.1074/jbc.M110.213728. Epub 2011 Feb 18.
The tumor suppressor protein BRCA1 is a constituent of several different protein complexes and is required for homology-directed repair (HDR) of DNA double strand breaks (DSBs). The most recently discovered BRCA1-RAP80 complex is recruited to ubiquitin structures on chromatin surrounding the break. Deficiency of any member of this complex confers hypersensitivity to DNA-damaging agents by undefined mechanisms. In striking contrast to other BRCA1-containing complexes that are known to promote HDR, we demonstrate that the BRCA1-RAP80 complex restricts end resection in S/G(2) phase of the cell cycle, thereby limiting HDR. RAP80 or BRCC36 deficiency resulted in elevated Mre11-CtIP-dependent 5' end resection with a concomitant increase in HDR mechanisms that rely on 3' single-stranded overhangs. We propose a model in which the BRCA1-RAP80 complex limits nuclease accessibility to DSBs, thus preventing excessive end resection and potentially deleterious homology-directed DSB repair mechanisms that can impair genome integrity.
抑癌蛋白 BRCA1 是几种不同蛋白复合物的组成部分，是同源定向修复（HDR）双链 DNA 断裂（DSBs）所必需的。最近发现的 BRCA1-RAP80 复合物被招募到断裂周围染色质上的泛素结构上。该复合物的任何成员缺失都会通过未定义的机制导致对 DNA 损伤剂的超敏反应。与已知促进 HDR 的其他包含 BRCA1 的复合物形成鲜明对比的是，我们证明 BRCA1-RAP80 复合物在细胞周期的 S/G2 期限制末端切除，从而限制 HDR。RAP80 或 BRCC36 的缺失导致 Mre11-CtIP 依赖性 5'端切除增加，同时增加依赖 3'单链突出的 HDR 机制。我们提出了一个模型，其中 BRCA1-RAP80 复合物限制了对 DSB 的核酸酶可及性，从而防止过度的末端切除和潜在有害的同源定向 DSB 修复机制，这些机制可能会损害基因组完整性。
