COMMD4 Functions with the Histone H2A-H2B Dimer for the Timely Repair of DNA Double Strand Breaks

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-homologousend-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.

COMMD1, from the Repair of DNA Double Strand Breaks, to a Novel Anti-Cancer Therapeutic Target

“…A single unrepaired DSB in a cell can be cytotoxic [22,47], additionally mutations or down-regulation of DNA repair proteins, associated with the repair of DSBs, are strongly linked with inherited cancer risk (BRCA1, BRCA2, ATM) [48][49][50][51]. Here, as we confirmed a role for COMMD1 in the repair of DSBs and as COMMD4 was previously shown to function in the repair of DSBs [35] and additionally a potential therapeutic target and prognostic factor in NSCLC [36], we investigated a similar role for COMMD1 in NSCLC. Initially, the expression of COMMD1 transcripts were evaluated using bioinformatic analysis of The Cancer Genome Atlas (TCGA) datasets (Figure 2A-E).…”

“…COMMD proteins containing a C-terminal COMM domain are novel potential anti-cancer therapeutic targets and prognostic markers [ 30 , 31 , 35 ]. The expression of COMMD4 [ 36 ] and COMMD9 were previously assessed in NSCLC [ 37 ].…”

“…COMMD1 has previously been shown to interact with other COMMD proteins, especially COMMD3, 4 and 6 [ 31 ]. As COMMD4 has been shown to directly function in DNA repair by regulating H2B monoubiquitination [ 35 ], it is likely that COMMD1 functions in a complex with COMMD4 to regulate this process.…”

“…Recently, COMMD4 was shown to be a novel DNA repair protein required for the timely repair of DSBs [ 35 ]. COMMD4-depleted cells were hypersensitive to DNA damaging agents and were unable to repair DSBs efficiently.…”

Defining COMMD4 as an anti-cancer therapeutic target and prognostic factor in non-small cell lung cancer

“…[54][55][56] We have recently demonstrated that COMMD4 functions by regulating the monoubiquitination of H2B, following the induction of DNA double-strand breaks. 57 We show that COMMD4 functions to limit the extent of epigenetic modification of the chromatin around the break site. Depletion of COMMD4 leads to a loss of RNF20/40 regulation and uncontrolled chromatin remodelling.…”