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.

Keywords: DNA repair; chromatin; histone modifications; ubiquitination.

Figure 1

Summary of histone lysine ubiquitination and deubiquitination enzymes involved in DNA damage response. The E3 enzymes are listed above the ubiquitination site, whereas the deubiquitinating enzymes are listed below.

Figure 2

Model of H2AK13/15 ubiquitination and reader proteins in the DNA damage response. RNF168-induced H2AK13/15 ubiquitination leads to the activation of the NHEJ (53BP1) or HR (BRCA1/BARD1) pathway. RNF8-RNF168 induced K63-linked chains to recruit the BRCA1-A complex (RAP80/BRCA1) and restrict the HR pathway.