BBAP Monoubiquitylates Histone H4 at Lysine 91 and Selectively Modulates the DNA Damage Response

Abstract

Summary Although the BBAP E3 ligase and its binding partner, BAL, are overexpressed in chemotherapy-resistant lymphomas, the role of these proteins in DNA damage responses remains undefined. Since BAL proteins modulate promoter-coupled transcription and contain structural motifs associated with chromatin remodeling and DNA repair, we reasoned that the BBAP E3 ligase might target nucleosomal proteins. Herein, we demonstrate that BBAP selectively monoubiquitylates histone H4 lysine 91 and protects cells exposed to DNA damaging agents. Disruption of BBAP-mediated monoubiquitylation of histone H4K91 is associated with the loss of chromatin-associated H4K20 methylase, mono- and dimethyl H4K20, and a delay in the kinetics of 53BP1 foci formation at sites of DNA damage. Since 53BP1 localizes to DNA damage sites, in part, via an interaction with dimethyl H4K20, these data directly implicate BBAP in the monoubiquitylation and additional post-translational modification of histone H4 and an associated DNA damage response.

STEAP1 Is Associated with the Invasive and Oxidative Stress Phenotype of Ewing Tumors

“…ADIPOR1 is the cognate receptor for adiponectin, which stimulates proliferation of hematopoietic stem cells (48). Although the precise function of the ubiquitin ligase DTX3L is not defined, recent work suggests that DTX3L monoubiquitylates histone H4 lysine 91 and thereby protects DNA from ROS (39). Here, we show that these genes are highly inducible by ROS and regulated by STAT1.…”

“…We choose MMP-1, ADIPOR1, and DTX3L for follow-up due to their high expression in Ewing tumors and their involvement in oxidative stress responses (34,38,39). Notably, (Fig.…”

PR-Set7 and H4K20me1: at the crossroads of genome integrity, cell cycle, chromosome condensation, and transcription

“…Furthermore, Skp2 was shown to be responsible for PR-Set7 degradation after UV damage, outside the chromatin context (Oda et al 2010). BBAP, another E3 ligase, also regulates PR-Set7 protein levels (Yan et al 2009). However, neither Skp2 nor BBAP have been shown to directly ubiquitinate PR-Set7.…”

Histone modifications in DNA damage response

“…H4K20 methyltransferase MMSET (Wolf-Hirschhorn syndrome candidate 1) regulates the induction of H4K20 methylation on histones around double-strand breaks, which in turn facilitates 53BP1 recruitment (Hajdu et al, 2011;Pei et al, 2011). In addition to MMSET, another two H4K20 methyltransferases Set8 and Set9 are also responsible for H4K20 methylation and the recruitment of 53BP1 (Dulev et al, 2014;Greeson et al, 2008;Oda et al, 2010;Sanders et al, 2004;Yan et al, 2009). Similar to H3K79 methylation, H4K20 methylation recruits 53BP1 via its tandem Tudor domain as well (Botuyan et al, 2006).…”

“…However, the relationship between H2A/H2AX ubiquitination and H2AX is not clear. Moreover, some other ubiquitin E3 ligases, such as B-lymphoma and BAL-associated protein (BBAP) (Yan et al, 2009), RNF20-RNF40 heterodimer (Moyal et al, 2011;Nakamura et al, 2011), Cul4-DDBRoc1 and checkpoint with forkheadassociated (FHA) and RING finger domain protein (CHFR) , have been shown to be involved in his-tone ubiquitination in response to DNA damage as well.…”