Abstract：
Homologous recombination (HR) is a high-fidelity DNA double-strand break (DSB) repair pathway. Both familial and somatic loss of function mutation(s) in various HR genes predispose to a variety of cancer types, underscoring the importance of error-free repair of DSBs in human physiology. While environmental sources of DSBs have been known, more recent studies have begun to uncover the role of endogenous base damage in leading to these breaks. Base damage repair intermediates often consist of single-strand breaks, which if left unrepaired, can lead to DSBs as the replication fork encounters these lesions. This review summarizes various sources of endogenous base damage and how these lesions are repaired. We highlight how conversion of base repair intermediates, particularly those with 5\'or 3\' blocked ends, to DSBs can be a predominant source of genomic instability in HR-deficient cancers. We also discuss how endogenous base damage and ensuing DSBs can be exploited to enhance the efficacy of Poly (ADP-ribose) polymerase inhibitors (PARPi), that are widely used in the clinics for the regimen of HR-deficient cancers.
摘要：
同源重组(HR)是高保真DNA双链断裂(DSB)修复途径。各种HR基因中的家族性和体细胞性功能缺失突变易患多种癌症类型，强调DSB无差错修复在人体生理中的重要性。虽然已经知道DSB的环境来源，最近的研究已经开始揭示内源性碱基损伤在导致这些断裂中的作用。碱基损伤修复中间体通常由单链断裂组成，如果没有修复，当复制叉遇到这些病变时，可能会导致DSB。这篇综述总结了内源性碱基损伤的各种来源以及如何修复这些损伤。我们重点介绍了如何转换基础修复中间体，特别是那些有5'或3'阻塞的末端，DSB可能是HR缺陷型癌症中基因组不稳定性的主要来源。我们还讨论了如何利用内源性碱基损伤和随后的DSB来增强聚（ADP-核糖）聚合酶抑制剂（PARPi）的功效，在临床上广泛用于HR缺陷癌症的治疗方案。
