DNA-Histone Cross-Links: Formation and Repair.

Manideep C Pachva,Bakhyt T Matkarimov,Alexei F Kisselev,Regina Groisman,Murat Saparbaev

doi:10.3389/fcell.2020.607045

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.

Highlights

Cellular DNA is constantly altered by endogenous and exogenous factors, resulting in tens of thousands of lesions in a human cell every day (Lindahl, 1993)
Assuming that active base excision repair (BER) can generate an excess number of AP sites as repair intermediates of DNA glycosylases, this repair pathway might be one of the major factors in the formation of DNA-histone cross-links (DHC) in cells
A recent discovery of the role of DNA glycosylases of the Nei-family in repair of bulky inter-strand DNA cross-links (ICLs) suggests that the BER pathway may participate in removal of AP site-induced DHCs (Couvé-Privat et al, 2007; Semlow et al, 2016; Martin et al, 2017)

Summary

Introduction

Cellular DNA is constantly altered by endogenous and exogenous factors, resulting in tens of thousands of lesions in a human cell every day (Lindahl, 1993). The covalently bound protein could be detected and degraded to a small peptide by cell proteolytic machinery, such as the specialized proteases SPRTN/Wss1, Ddi1, and GCNA1, or by proteasome, an ATP-dependent multi-subunit protease complex, whereas the damaged DNA component is detected and repaired in the NER, BER, HR, NHEJ, and FA pathways.

Results

Conclusion