Seol Ja-Hwan, Shim Eun Yong, Lee Sang Eun
Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, United States.
Department of Radiation Oncology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, United States.
Mutat Res. 2018 May;809:81-87. doi: 10.1016/j.mrfmmm.2017.07.002. Epub 2017 Jul 16.
DNA double-strand breaks (DSBs) are induced by a variety of genotoxic agents, including ionizing radiation and chemotherapy drugs for treating cancers. The elimination of DSBs proceeds via distinctive error-free and error-prone pathways. Repair by homologous recombination (HR) is largely error-free and mediated by RAD51/BRCA2 gene products. Classical non-homologous end joining (C-NHEJ) requires the Ku heterodimer and can efficiently rejoin breaks, with occasional loss or gain of DNA information. Recently, evidence has unveiled another DNA end-joining mechanism that is independent of recombination factors and Ku proteins, termed alternative non-homologous end joining (A-NHEJ). While A-NHEJ-mediated repair does not require homology, in a subtype of A-NHEJ, DSB breaks are sealed by microhomology (MH)-mediated base-pairing of DNA single strands, followed by nucleolytic trimming of DNA flaps, DNA gap filling, and DNA ligation, yielding products that are always associated with DNA deletion. This highly error-prone DSB repair pathway is termed microhomology-mediated end joining (MMEJ). Dissecting the mechanisms of MMEJ is of great interest because of its potential to destabilize the genome through gene deletions and chromosomal rearrangements in cells deficient in canonical repair pathways, including HR and C-NHEJ. In addition, evidence now suggests that MMEJ plays a physiological role in normal cells.
DNA双链断裂（DSB）可由多种基因毒性试剂诱导产生，包括电离辐射和用于治疗癌症的化疗药物。DSB的消除通过独特的无差错和易出错途径进行。同源重组（HR）修复在很大程度上是无差错的，由RAD51/BRCA2基因产物介导。经典的非同源末端连接（C-NHEJ）需要Ku异二聚体，并且可以有效地重新连接断裂处，偶尔会丢失或获得DNA信息。最近，有证据揭示了另一种独立于重组因子和Ku蛋白的DNA末端连接机制，称为替代性非同源末端连接（A-NHEJ）。虽然A-NHEJ介导的修复不需要同源性，但在A-NHEJ的一个亚型中，DSB断裂通过DNA单链的微同源性（MH）介导的碱基配对进行封闭，随后对DNA侧翼进行核酸酶修剪、DNA缺口填充和DNA连接，产生总是与DNA缺失相关的产物。这种高度易出错的DSB修复途径称为微同源性介导的末端连接（MMEJ）。剖析MMEJ的机制具有重要意义，因为它有可能通过在缺乏经典修复途径（包括HR和C-NHEJ）的细胞中发生基因缺失和染色体重排来破坏基因组的稳定性。此外，现在有证据表明MMEJ在正常细胞中发挥生理作用。
