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DNA-Histone Cross-Links: Formation and Repair

Abstract : The nucleosome is a stretch of DNA wrapped around a histone octamer. Electrostatic interactions and hydrogen bonds between histones and DNA are vital for the stable organization of nucleosome core particles, and for the folding of chromatin into more compact structures, which regulate gene expression via controlled access to DNA. As a drawback of tight association, under genotoxic stress, DNA can accidentally cross-link to histone in a covalent manner, generating a highly toxic DNA-histone cross-link (DHC). DHC is a bulky lesion that can impede DNA transcription, replication, and repair, often with lethal consequences. The chemotherapeutic agent cisplatin, as well as ionizing and ultraviolet irradiations and endogenously occurring reactive aldehydes, generate DHCs by forming either stable or transient covalent bonds between DNA and side-chain amino groups of histone lysine residues. The mechanisms of DHC repair start to unravel, and certain common principles of DNA-protein cross-link (DPC) repair mechanisms that participate in the removal of cross-linked histones from DNA have been described. In general, DPC is removed via a two-step repair mechanism. First, cross-linked proteins are degraded by specific DPC proteases or by the proteasome, relieving steric hindrance. Second, the remaining DNA-peptide cross-links are eliminated in various DNA repair pathways. Delineating the molecular mechanisms of DHC repair would help target specific DNA repair proteins for therapeutic intervention to combat tumor resistance to chemotherapy and radiotherapy.
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Contributor : Murat Saparbaev Connect in order to contact the contributor
Submitted on : Wednesday, November 17, 2021 - 1:20:19 PM
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Manideep C Pachva, Alexei F Kisselev, Bakhyt T Matkarimov, Murat A Saparbaev, Regina Groisman. DNA-Histone Cross-Links: Formation and Repair. Frontiers in Cell and Developmental Biology, Frontiers media, 2020, 8, pp.647045. ⟨10.3389/fcell.2020.607045⟩. ⟨hal-03432690⟩



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