DNA-HISTONE CROSS-LINKS: FORMATION AND REPAIR
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Date
2020-12-21
Authors
Pachva, Manideep C.
Kisselev, Alexei F.
Matkarimov, Bakhyt T.
Saparbaev, Murat
Groisman, Regina
Journal Title
Journal ISSN
Volume Title
Publisher
Frontiers Media
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 crosslink 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.
Description
Keywords
DNA-histone cross-link, nucleosome core particle, chromatin, genome instability, spartan protease, proteasome, DNA repair, Research Subject Categories::NATURAL SCIENCES::Biology
Citation
Pachva, M. C., Kisselev, A. F., Matkarimov, B. T., Saparbaev, M., & Groisman, R. (2020). DNA-histone cross-links: Formation and repair. Frontiers in Cell and Developmental Biology, 8, 607045.