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.
Highlights
Genomic stability is critical for normal cellular function and its deregulation is a universal hallmark of cancer
We found that cells depleted of COMMD4 were sensitive to several DNA damaging agents that cause double-strand breaks (DSBs) and are defective in their repair of DSBs
We utilised several assays to measure the repair of DSBs by non-homologous end-joining (NHEJ) and homologous recombination (HR) in control and COMMD4-depleted cells, which indicated that both NHEJ and HR are functionally impaired in the absence of COMMD4
Summary
Genomic stability is critical for normal cellular function and its deregulation is a universal hallmark of cancer. Chromatin remodelling plays an essential role in the functioning of all cellular processes involving DNA, including transcription, DNA replication and DNA repair and involves the concerted action of histone post-translational modifications, including, phosphorylation, methylation, acetylation and ubiquitination[9]. Such responses upon the induction of DNA DSBs include the phosphorylation and ubiquitination of H2AX, as well as the ubiquitination of H2A by RNF8 and RNF168. COMMD4-deficient cells are genomically unstable, hypersensitive to DNA damaging agents and are unable to efficiently repair DSBs. Our data demonstrates a specific role for COMMD4 in regulating the monoubiquitination of H2B at sites of DNA DSBs, by binding to the histone H2A-H2B dimer
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