Abstract
How chromatin dynamics is regulated to ensure efficient DNA repair remains to be understood. Here, we report that the ubiquitin-specific protease USP11 acts as a histone deubiquitinase to catalyze H2AK119 and H2BK120 deubiquitination. We showed that USP11 is physically associated with the chromatin remodeling NuRD complex and functionally involved in DNA repair process. We demonstrated that USP11-mediated histone deubiquitination and NuRD-associated histone deacetylation coordinate to allow timely termination of DNA repair and reorganization of the chromatin structure. As such, USP11 is involved in chromatin condensation, genomic stability, and cell survival. Together, these observations indicate that USP11 is a chromatin modifier critically involved in DNA damage response and the maintenance of genomic stability.
Highlights
Eukaryotic cells evolve highly efficient DNA repair system to guide the integrity of the genome in response to a plethora of exogenous as well as endogenous DNA insults
It is becoming increasingly clear that histone modifications such as ubiquitination and subsequent recruitment of DNA repair proteins are the integral parts of the regulatory network in response to DNA damages [5,17,18,29], and a number of deubiquitinating enzymes (DUBs) have been implicated in DNA repair process [14,26,27,48–52]
In order to have a general view of the multitude of DUBs that potentially participate in mammalian double-strand breaks (DSBs) response, we systematically screened 81 DUBs for their role in H2BK120 deubiquitination or in ionizing radiation-induced foci (IRIF) formation of 53BP1, a well-known DNA damage response (DDR) factor that is recruited to DNA damage sites and forms readily visualized IRIF [53]
Summary
Eukaryotic cells evolve highly efficient DNA repair system to guide the integrity of the genome in response to a plethora of exogenous as well as endogenous DNA insults. DNA double-strand breaks (DSBs), which are exceedingly dangerous chromosomal lesions as they entail physical cleavage of the DNA backbone, trigger two mechanistically distinct pathways of DNA damage response (DDR), non-homologous end-joining (NHEJ) and homologous recombination (HR) [2–4]. Both the initial response at DSB sites and subsequent spreading of the DNA damage alarms involve extensive dynamic posttranslational modifications (PTMs) of histones and nonhistones, including phosphorylation and ubiquitylation [5– 7]. A systematic screening of DUB for their roles in the maintenance of genome integrity indicates that as many as 23 DUBs are potentially involved in DSB repair and the G2/M checkpoint [15]. The multitude and magnitude of DUBs impacting on DNA damage response need experimental validation, and the substrates and exact functions of these DUBs in the maintenance of genome stability need further elucidation
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