DNA末端保护盾Shieldin在DNA损伤修复中的研究进展

Recent advances of Shieldin in DNA damage repair as a DNA-end protector

同源重组(homologous recombination,HR)与非同源末端连接(non-homologous end joining,NHEJ)的选择机制是DNA双链断裂损伤修复的前沿科学问题。末端切除是HR修复的标志性事件,53BP1通过竞争BRCA1介导的末端切除将修复途径从HR转向NHEJ进行。近年来,多个课题组同时发现并证实Shieldin复合物是53BP1介导的两种修复途径选择的下游效应因子。Shieldin是由Rev7、SHLD1(C20orf196)、SHLD2(FAM35A)与SHLD3(CTC-534A2.2)组成的复合体蛋白,能够限制末端切除并抑制HR修复,并以53BP1依赖的方式促进NHEJ修复。该文对Shieldin结构组装、工作与活性调节机制的研究进展进行综述,同时关注Shieldin对肿瘤治疗干预的临床价值,以期为肿瘤耐药机制与逆转耐药研究提供新的线索分子。

The selection mechanism of homologous recombination(HR) and non-homologous end joining(NHEJ) is a cutting-edge scientific issue in DNA double-strand break damage repair. DNA-end resection has a major role in regulating the balance between HR and NHEJ repair. 53 BP1 competes with BRCA1-mediated end resection and directs repair pathway choice from HR to NHEJ. In recent years, multiple research groups have confirmed that Shieldin complex acts as a downstream effector of 53 BP1. Shieldin is a four-subunit protein complex which consists of Rev7, SHLD1(C20 orf196), SHLD2(FAM35 A) and SHLD3(CTC-534 A2.2), which can inhibit the end resection-mediated HR, and promote the NHEJ repair in a 53 BP1-dependent manner. This article reviews the research progress and future advance of Shieldin, including the assembly and regulatory machinery, as well as clinical significance for tumor therapy, hoping to provide new molecular clues for understanding and over coming chemoresistance in tumor patients.