Magee-Womens Research Institute, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pennsylvania 15213.
Magee-Womens Research Institute, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pennsylvania 15213
Genetics. 2018 Nov;210(3):843-856. doi: 10.1534/genetics.118.301402. Epub 2018 Sep 21.
Double-strand breaks (DSBs) are among the most deleterious lesions DNA can endure. Yet, DSBs are programmed at the onset of meiosis, and are required to facilitate appropriate reduction of ploidy in daughter cells. Repair of these breaks is tightly controlled to favor homologous recombination (HR)-the only repair pathway that can form crossovers. However, little is known about how the activities of alternative repair pathways are regulated at these stages. We discovered an unexpected synthetic interaction between the DSB machinery and strand-exchange proteins. Depleting the DSB-promoting factors HIM-5 and DSB-2 suppresses the formation of chromosome fusions that arise in the absence of RAD-51 or other strand-exchange mediators. Our investigations reveal that nonhomologous and theta-mediated end joining (c-NHEJ and TMEJ, respectively) and single strand annealing (SSA) function redundantly to repair DSBs when HR is compromised, and that HIM-5 influences the utilization of TMEJ and SSA.
双链断裂 (DSB) 是 DNA 所能承受的最具破坏性的损伤之一。然而，在减数分裂开始时就会出现 DSB，并需要促进子细胞中适当的倍性减少。这些断裂的修复受到严格控制，以有利于同源重组 (HR)——唯一能够形成交叉的修复途径。然而，对于这些阶段替代修复途径的活性是如何被调控的，我们知之甚少。我们发现了 DSB 机器和链交换蛋白之间出乎意料的合成相互作用。耗尽 DSB 促进因子 HIM-5 和 DSB-2 会抑制在没有 RAD-51 或其他链交换介质的情况下出现的染色体融合的形成。我们的研究表明，非同源和θ介导的末端连接 (c-NHEJ 和 TMEJ，分别) 和单链退火 (SSA) 在 HR 受损时可冗余地修复 DSB，并且 HIM-5 影响 TMEJ 和 SSA 的利用。
