Repair pathway choice for double-strand breaks

Abstract

<jats:title>Abstract</jats:title> <jats:p>Deoxyribonucleic acid (DNA) is at a constant risk of damage from endogenous substances, environmental radiation, and chemical stressors. DNA double-strand breaks (DSBs) pose a significant threat to genomic integrity and cell survival. There are two major pathways for DSB repair: nonhomologous end-joining (NHEJ) and homologous recombination (HR). The extent of DNA end resection, which determines the length of the 3′ single-stranded DNA (ssDNA) overhang, is the primary factor that determines whether repair is carried out via NHEJ or HR. NHEJ, which does not require a 3′ ssDNA tail, occurs throughout the cell cycle. 53BP1 and the cofactors PTIP or RIF1-shieldin protect the broken DNA end, inhibit long-range end resection and thus promote NHEJ. In contrast, HR mainly occurs during the S/G2 phase and requires DNA end processing to create a 3′ tail that can invade a homologous region, ensuring faithful gene repair. BRCA1 and the cofactors CtIP, EXO1, BLM/DNA2, and the MRE11–RAD50–NBS1 (MRN) complex promote DNA end resection and thus HR. DNA resection is influenced by the cell cycle, the chromatin environment, and the complexity of the DNA end break. Herein, we summarize the key factors involved in repair pathway selection for DSBs and discuss recent related publications.</jats:p>

TEX10 Promotes the Tumorigenesis and Radiotherapy Resistance of Urinary Bladder Carcinoma by Stabilizing XRCC6

“…Such a versatile regulating protein participates into a variety of nuclear processes, such as DNA repair, telomere maintenance, and apoptosis [36][37][38][39]. The DNA double-strand break (DSB) repair channels are essential for the maintenance of eukaryote genetic integrity, including homologous recombination and nonhomologous end joining (NHEJ) [33,40]. Ku proteins as the critical NHEJ factors participate in the DNA NHEJ DSB channel.…”

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“…Importantly, these 53BP1 foci were also proposed to locally hold the chromatin architecture, to keep it in a configuration favorable for repair ( Ochs et al, 2019 ). Therefore, altogether, the different actors involved in this structuring step, although not directly participating to the resolution of the DNA lesion, can improve the efficiency of the repair and also potentially dictate the pathway that will be chosen for restoring the genome ( Xu and Xu, 2020 ). Indeed, while the early chromatin “breathing” triggered by the joint activities of CHD7 and HDAC1/2 promotes DSB repair by non-homologous end-joining (NHEJ) ( Rother et al, 2020 ), chromatin remodeling via CHD4 rather seems to favor DSB repair by homologous recombination ( Qi et al, 2016 ; Smith et al, 2018 ).…”

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“…3) Repair of double-strand breaks (DSBs). Xu and Xu discussed the pathway choice for DSBs based on DNA end condition, which is antagonistically controlled by BRCA1 and 53BP1, and other regulatory factors such as cell cycle and chromatin environment (6). Kawale and Sung focused on the proteins and mechanistic function of the homologous recombination (HR) pathway, describing four major stages: DNA end resection, presynaptic filament assembly, DNA strand invasion and repair DNA synthesis (7).…”