Nucleosome acidic patch promotes H2AX and H2A ubiquitination and DNA damage signaling (925.1)

Abstract

Post‐translational modifications of histones, including ubiquitination, participate in the chromatin response to DNA damage. Indeed, RNF168 and RING1B/BMI1 function in the DNA damage response by ubiquitinating H2A/H2AX on Lys‐13/15 and Lys‐118/119, respectively. How the ubiquitin pathway engages chromatin to provide site‐specificity between histone residues is undefined. Here we identify the nucleosome acid patch as a critical chromatin mediator of H2A/H2AX ubiquitination. The acidic patch is required for RNF168‐ and RING1B/BMI1‐dependent H2A/H2AXub in vivo. The acidic patch functions within the nucleosome as nucleosomes containing a mutated acidic patch exhibit defective H2A/H2AXub by RNF168 and RING1B/BMI1 in vitro. Furthermore, direct perturbation of the nucleosome acidic patch in vivo by the expression of an acidic patch interacting viral peptide, LANA, results in defective H2AXub and DNA damage responses. The acidic patch therefore is a critical nucleosome feature that may serve as a scaffold to integrate multiple ubiquitin signals on chromatin to compose selective ubiquitinations on histones for DNA damage signaling and repair. We aim to further our understanding of the molecular mechanisms by which the nucleosome acidic patch mediates histone modifications to orchestrate DNA damage signaling.Grant Funding Source: Supported by CPRIT (R1116).