DNA Double Strand Break Repair and Its Control by Nucleosome Remodeling

Abstract

DNA double strand breaks (DSBs) are repaired in eukaryotes by one of several cellular mechanisms. The decision-making process controlling DSB repair takes place at the step of DNA end resection, the nucleolytic processing of DNA ends, which generates single-stranded DNA overhangs. Dependent on the length of the overhang, a corresponding DSB repair mechanism is engaged. Interestingly, nucleosomes—the fundamental unit of chromatin—influence the activity of resection nucleases and nucleosome remodelers have emerged as key regulators of DSB repair. Nucleosome remodelers share a common enzymatic mechanism, but for global genome organization specific remodelers have been shown to exert distinct activities. Specifically, different remodelers have been found to slide and evict, position or edit nucleosomes. It is an open question whether the same remodelers exert the same function also in the context of DSBs. Here, we will review recent advances in our understanding of nucleosome remodelers at DSBs: to what extent nucleosome sliding, eviction, positioning and editing can be observed at DSBs and how these activities affect the DSB repair decision.

Research Progress on the Anticancer Activities and Mechanisms of Polysaccharides From Ganoderma

“…Ganoderma polysaccharides can target DSB repair kinases ATM and DNA-PK, thus inhibiting cancer pathogenesis ( Figure 1 ). DSB is a major threat to genomic integrity and may arise from the presence of genotoxic agents ( Karl et al, 2022 ). Cells adopt several DSB repair mechanisms including homologous recombination (HR), non-homologous end-joining (NHEJ) and single strand annealing (SSA) that involve a number of mediators and effectors [e.g., ATM, breast cancer susceptibility gene 1/2 (BRCA1/2), checkpoint kinase 1/2 (CHK1/2) and DNA-PK] ( Blasiak, 2021 ).…”

DNA-Damage-Repair Gene Alterations in Genitourinary Malignancies

“…DSBs are a highly toxic form of DNA damage, arising from intrinsic and extrinsic sources [2]. Eukaryotes are equipped with several mechanisms to repair DSBs, including nonhomologous end-joining, microhomology-mediated end-joining, or homologous recombination (HR) repair (HRR), among others [3]. HR is a tightly regulated molecular mechanism essential for maintaining genomic stability by repairing DSBs or lesions that stall DNA replication forks.…”

The Chromatin Landscape around DNA Double-Strand Breaks in Yeast and Its Influence on DNA Repair Pathway Choice

“…The response to DSBs should be considered within the context of chromatin, a highly organized structure in which the DNA is wrapped around octamers of four core histones H2A, H2B, H3, and H4 forming the nucleosomes [ 10 ]. Nucleosomes impose a barrier to the DNA repair machinery, particularly to DNA end resection, and nucleosomal organization around a DSB must be disrupted or modified to allow proper repair [ 14 ]. In addition, the position of a DSB in the genome and the chromatin structure around the DSB affect its recombination properties.…”

“…Chromatin structure around a DSB can be modified by removing entire nucleosomes, thanks to the action of chromatin remodeling factors, and/or by modifying histones, thus increasing chromatin flexibility and accessibility of repair enzymes to the DSB [ 10 , 14 ]. Histones are subjected to a vast array of post-translational modifications (PTMs) such as phosphorylation, acetylation, methylation, and ubiquitylation that target histone tails [ 16 ].…”