53BP1 Binds DNA Damage–Induced H2AK15UB

Following DNA double-strand breaks (DSB), multiple proteins are recruited to chromatin in a sequential manner to mediate various aspects of the DNA damage response. 53BP1 is a chromatin-binding protein that is recruited to DSBs to promote DNA repair by nonhomologous end joining. 53BP1 binding to chromatin is mediated by its tandem Tudor domain, which recognizes dimethylated histone H4 lysine 20 (H4K20me2). However, because 53BP1 recruitment to DSBs also requires the E3 ubiquitin ligase RNF168, exactly how ubiquitin promotes the accumulation of a methyl-histone binding protein at break sites remains a mystery. To better understand the ubiquitin-dependent mechanism of 53BP1 recruitment to DSBs, Fradet-Turcotte and colleagues turned to the Schizosaccharomyces pombe 53BP1 ortholog, Crb2. Like human 53BP1, Crb2 has a tandem Tudor domain that binds H4K20me2, but fission yeast do not have a RNF168 homolog, and Crb2 does not form DNA damage-induced foci when expressed in human cells. Mapping of the regions of human 53BP1 that could restore foci formation when fused to Crb2 identified a region C-terminal to the Tudor domain the authors termed the ubiquitin-dependent recruitment (UDR) motif. The UDR was required for 53BP1 accumulation at DSBs as well as for its downstream roles in the DNA damage response, and specifically interacted with ubiquitinated histone H2A within polynucleosomes. 53BP1 binding was specific to monomeric nucleosome core particles containing H4K20me2 and ubiquitinated histone H2A lysine 15 (H2AK15Ub). Given that RNF168 can also ubiquitinate H2AK13Ub, this finding suggests that other ubiquitin marks on histones may have their own sets of readers, thus expanding the repertoire of instructive histone marks. The identification of 53BP1 as a bivalent reader of H4K20me2 and H2AK15Ub therefore explains how ubiquitination recruits 53BP1 to DSBs and illustrates the importance of distinct histone modifications in orchestrating the DNA damage response.

Fradet-Turcotte A, Canny MD, Escribano-Díaz C, Orthwein A, Leung CC, Huang H, et al. 53BP1 is a reader of the DNA damage-induced H2A Lys15 ubiquitin mark. Nature 2013;499:50–4.

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