USP11 acts as a histone deubiquitinase functioning in chromatin reorganization during DNA repair

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.

Regulation of Histone Ubiquitination in Response to DNA Double Strand Breaks

“…In support of this, RNF8 depleted cells showed a delay in IR-induced 53BP1 foci, as expected, while depletion of USP11 led to hyperaccumulation of ubiquitin conjugates and 53BP1 [ 33 ]. Although this work argues that USP11 is specific for ubiquitinated γH2AX, others have shown USP11 activity towards H2AK119ub1 as well as H2BK120ub1 [ 137 ]. In these studies, the defects in DSB repair and IR sensitivity observed upon loss of USP11 were restored when USP11 was co-depleted with either BMI1 or RNF20 (involved in catalyzing H2AK119ub1 and H2BK120ub1, respectively) [ 137 ].…”

“…Although this work argues that USP11 is specific for ubiquitinated γH2AX, others have shown USP11 activity towards H2AK119ub1 as well as H2BK120ub1 [ 137 ]. In these studies, the defects in DSB repair and IR sensitivity observed upon loss of USP11 were restored when USP11 was co-depleted with either BMI1 or RNF20 (involved in catalyzing H2AK119ub1 and H2BK120ub1, respectively) [ 137 ]. This reveals several additional mechanisms by which USP11 may influence DSB repair including transcriptional regulation and chromatin conformation.…”

“…Further solidifying a role for USP3 in the DSB response, USP3-null mice are more sensitive to total body irradiation when compared to their WT counterparts [ 132 ]. Interestingly, USP3 was a hit in an RNAi screen identifying DUBs that regulate H2BK120ub and 53BP1 foci [ 137 ]. While the activity of USP3 at this residue has not been thoroughly investigated in the context of the DSB response, USP3 has been shown to regulate levels of ubiquitinated H2B in vitro and in vivo (albeit to a lesser extent than ubiquitinated H2A) [ 110 , 132 , 134 , 137 ].…”

“…The interactions between USP11, NuRD, and chromatin are increased following IR, suggesting USP11 may be recruited to sites of DSBs to aid in the regulation of gene expression. Additionally, USP11 depletion led to increased sensitivity to micrococcal nuclease following IR when compared to controls, and therefore may be able to modulate DNA repair factor access to chromatin as well [ 137 ]. From this body of work, it is clear that the role of USP11 in the repair of DSBs is much more complex than what is currently understood.…”

USP11 deubiquitinates monoubiquitinated SPRTN to repair DNA-protein crosslinks

“…USP11 participates in processes such as TGFβ signaling, pro-inflammatory signaling, viral replication and NF-κB signaling by regulating the protein stability of various targets such as ARID1A, TβRII, CDKN2A, RAE1, XIAP, HPV16-E7 and IκBα (Luo et al, 2020, Deng et al, 2018, Jacko et al, 2016, Lin et al, 2008, Sun et al, 2010, Stockum et al, 2018. USP11 also functions in DSB repair, wherein USP11 deubiquitinates H2AX to regulate the recruitment of RAD51 and 53BP1 to damage foci (Ting et al, 2019, Yu et al, 2016. USP11 deubiquitinates PALB2 and promotes BRCA1-PALB2-BRCA2 complex formation (Orthwein et al, 2015).…”