Homologous Recombination-Mediated DNA Repair and Implications for Clinical Treatment of Repair Defective Cancers.
Homologous Recombination-Mediated DNA Repair and Implications for Clinical Treatment of Repair Defective Cancers.
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DOI：
10.1007/978-1-4939-9500-4_1
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发表时间：
2019
影响因子：
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通讯作者：
N. M. Reilly;B. Yard;D. Pittman
中科院分区：
文献类型：
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作者：
N. M. Reilly;B. Yard;D. Pittman
双链DNA断裂(DSB)是由电离辐射产生的，并在DNA加工过程中作为中间产物，如修复链间交链和折叠的复制叉子。这些潜在的有害DSB主要通过同源重组(HR)和非同源末端连接(NHEJ)DNA修复途径修复。HR使用同源模板来准确修复受损的DNA，而NHEJ使用微同源来紧密连接断裂。DSB的修复途径依赖于细胞周期的不同阶段，例如HR主要在S/G2期发挥作用，而NHEJ可以在任何细胞周期阶段修复DSB。翻译后修饰(PTM)通过酶的激活和精确定时的蛋白质募集和降解来促进特定通路和亚通路的活性。本章概述了DSB维修过程中发生的PTM。此外，还讨论了与HR缺陷癌症相关的临床表型，例如用于预测对聚(ADP-核糖)聚合酶抑制剂的反应的突变特征。了解这些过程将提供对基因组维持机制的洞察，并可能确定治疗干预的目标和新途径。
Double-strand DNA breaks (DSBs) are generated by ionizing radiation and as intermediates during the processing of DNA, such as repair of interstrand cross-links and collapsed replication forks. These potentially deleterious DSBs are repaired primarily by the homologous recombination (HR) and nonhomologous end joining (NHEJ) DNA repair pathways. HR utilizes a homologous template to accurately restore damaged DNA, whereas NHEJ utilizes microhomology to join breaks in close proximity. The pathway available for DSB repair is dependent upon the cell cycle stage; for example, HR primarily functions during the S/G2 stages while NHEJ can repair DSBs at any cell cycle stage. Posttranslational modifications (PTMs) promote activity of specific pathways and subpathways through enzyme activation and precisely timed protein recruitment and degradation. This chapter provides an overview of PTMs occurring during DSB repair. In addition, clinical phenotypes associated with HR-defective cancers, such as mutational signatures used to predict response to poly(ADP-ribose) polymerase inhibitors, are discussed. Understanding these processes will provide insight into mechanisms of genome maintenance and likely identify targets and new avenues for therapeutic interventions.