Department of Cancer Genetics and Epigenetics, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
Department of Cancer Genetics and Epigenetics, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
DNA Repair (Amst). 2022 Oct;118:103380. doi: 10.1016/j.dnarep.2022.103380. Epub 2022 Jul 30.
Chromosomal DNA double-strand breaks (DSBs) are the effective lesion of radiotherapy and other clastogenic cancer therapeutics, and are also the initiating event of many approaches to gene editing. Ligation of the DSBs by end joining (EJ) pathways can restore the broken chromosome, but the repair junctions can have insertion/deletion (indel) mutations. The indel patterns resulting from DSB EJ are likely defined by the initial structure of the DNA ends, how the ends are processed and synapsed prior to ligation, and the factors that mediate the ligation step. In this review, we describe key factors that influence these steps of DSB EJ in mammalian cells, which is significant both for understanding mutagenesis resulting from clastogenic cancer therapeutics, and for developing approaches to manipulating gene editing outcomes.
染色体 DNA 双链断裂 (DSBs) 是放疗和其他致裂癌症疗法的有效损伤，也是许多基因编辑方法的起始事件。通过末端连接 (EJ) 途径连接 DSB 可以修复断裂的染色体，但修复连接点可能会有插入/缺失 (indel) 突变。DSB EJ 产生的 indel 模式可能由 DNA 末端的初始结构、末端在连接前的加工和联会方式以及介导连接步骤的因素决定。在这篇综述中，我们描述了影响哺乳动物细胞 DSB EJ 的这些步骤的关键因素，这对于理解致裂癌症疗法导致的突变以及开发操纵基因编辑结果的方法都具有重要意义。
