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, Shu-Dong Zhang, Kenneth J. O’Byrne, Derek J. Richard

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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.
Original languageEnglish
Pages (from-to)484
JournalCommunications Biology
Issue number1
Early online date19 Apr 2021
Publication statusE-pub ahead of print - 19 Apr 2021


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