COMMD4 functions with the histone H2A-H2B dimer for the timely repair of DNA double-strand breaks
Amila Suraweera, Neha S. Gandhi, Sam Beard, Joshua T. Burgess, Laura V. Croft, Emma Bolderson, Ali Naqi, Nicholas W. Ashton, Mark N. Adams, Kienan I. Savage, Shudong Zhang, Kenneth J. O’Byrne, Derek J. Richard
Abstract
Genomic stability is critical for normal cellular function and its deregulation is a universal hallmark of cancer. Here we outline a previously undescribed role of COMMD4 in maintaining genomic stability, by regulation of chromatin remodelling at sites of DNA double-strand breaks. At break-sites, COMMD4 binds to and protects histone H2B from monoubiquitination by RNF20/RNF40. DNA damage-induced phosphorylation of the H2A-H2B heterodimer disrupts the dimer allowing COMMD4 to preferentially bind H2A. Displacement of COMMD4 from H2B allows RNF20/40 to monoubiquitinate H2B and for remodelling of the break-site. Consistent with this critical function, COMMD4-deficient cells show excessive elongation of remodelled chromatin and failure of both non-homologous-end-joining and homologous recombination. We present peptide-mapping and mutagenesis data for the potential molecular mechanisms governing COMMD4-mediated chromatin regulation at DNA double-strand breaks.