COMMD4 Functions with the Histone H2A-H2B Dimer for the Timely Repair of DNA Double Strand Breaks
60 Pages Posted: 10 Jan 2020 Sneak Peek Status: Under ReviewMore...
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 regulating of chromatin remodelling at sites of DNA double strand breaks (DSBs). We demonstrate that COMMD4 is initially recruited to DSBs by a direct-interaction with phosphorylated hSSB1. 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 monoubuquitinate H2B and for remodelling of the break-site. Consistent with this critical function, COMMD4-defficient cells show excessive elongation of remodelled chromatin and failure of both non-homologous-end-joining and homologous recombination. We present a model, developed by molecular dynamic simulation, peptide-mapping and mutagenesis for the potential molecular mechanisms governing COMMD4-mediated chromatin regulation at DSBs.
Keywords: H2A, H2B, H2A-H2B dimer, DNA double strand breaks, genomic stability, COMMD4
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