DNA Damage Response Regulation by Histone Ubiquitination

Abstract

Cells are constantly exposed to numerous genotoxic stresses that induce DNA damage. DNA double-strand breaks (DSBs) are among the most serious damages and should be systematically repaired to preserve genomic integrity. The efficiency of repair is closely associated with chromatin structure, which is regulated by posttranslational modifications of histones, including ubiquitination. Recent evidence shows crosstalk between histone ubiquitination and DNA damage responses, suggesting an integrated model for the systematic regulation of DNA repair. There are two major pathways for DSB repair, viz., nonhomologous end joining and homologous recombination, and the choice of the pathway is partially controlled by posttranslational modifications of histones, including ubiquitination. Histone ubiquitination changes chromatin structure in the vicinity of DSBs and serves as a platform to select and recruit repair proteins; the removal of these modifications by deubiquitinating enzymes suppresses the recruitment of repair proteins and promotes the convergence of repair reactions. This article provides a comprehensive overview of the DNA damage response regulated by histone ubiquitination in response to DSBs.

DNA Damage Response Alterations in Ovarian Cancer: From Molecular Mechanisms to Therapeutic Opportunities

“…Ubiquitination is an example of histone posttranslational modification important in the DDR. It has been described that this modification changes the chromatin structure in the vicinity of DSBs and serves as a platform to select and recruit repair proteins [262] The ATP-dependent mechanisms use the energy of ATP hydrolysis to disrupt the DNA-histone contacts and constitute most of the remodeling activity in the cell [47]. Four families of multi-subunit chromatin remodeling complexes have been described: SWI/SNF, INO80, CHD, and ISWI.…”

Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies

“…TP53‐associated H3K9 and H3K14 acetylation promotes TP53 transcription, 118 while monomethylation on H4K20 represses TP53 transcription by inhibiting nucleosome depolymerization 119,120 . High levels of H2B ubiquitination are often associated with DNA repair 121,122 . High methylation levels in the TP53 promoter region can hinder the binding of transcription factors and inhibit TP53 expression, leading to various cancers 123 .…”

“… 119 , 120 High levels of H2B ubiquitination are often associated with DNA repair. 121 , 122 High methylation levels in the TP53 promoter region can hinder the binding of transcription factors and inhibit TP53 expression, leading to various cancers. 123 DNA methyltransferase inhibitors such as 5‐aza‐2'‐deoxycytidine can downregulate methylation levels in the TP53 promoter region, facilitating the binding of transcription factors and promoting TP53 expression.…”

Maintaining chromosome and genome stability by the RPA–RNF20–SNF2H cascade

“…The interplay and cross talk between histone PTMs such as ubiquitination, methylation, and phosphorylation play an integral and crucial role in chromosome separation and DNA repair, as well as chromosome reorganization or remodeling ( 9 ). The Histone 2B mono-ubiquitination at Lysine 120 (H2B-K120ub) is primarily catalyzed by the heterodimeric RING Finger E3 ubiquitin ligase RNF20/RNF40 (the homolog of yeast Bre1) and the E2 ubiquitin-conjugating enzyme Rad6 ( 9 , 10 ). H2B-K120ub is implicated in various cellular processes, including chromatin remodeling, transcription regulation, DDR, stem cell differentiation, and tissue development ( 9 – 11 ).…”

“…The Histone 2B mono-ubiquitination at Lysine 120 (H2B-K120ub) is primarily catalyzed by the heterodimeric RING Finger E3 ubiquitin ligase RNF20/RNF40 (the homolog of yeast Bre1) and the E2 ubiquitin-conjugating enzyme Rad6 ( 9 , 10 ). H2B-K120ub is implicated in various cellular processes, including chromatin remodeling, transcription regulation, DDR, stem cell differentiation, and tissue development ( 9 – 11 ). A crucial downstream effector of H2B-K120ub is the ATP-dependent chromatin remodeler complex SNF2H and RSF1, which interacts with nucleosomes containing H2B-K120 and contributes to the regulation of chromatin remodeling and transcription ( 9 , 11 ).…”