COMMD4 functions with the histone H2A-H2B dimer for the timely repair of DNA double-strand breaks.
Amila SuraweeraNeha S GandhiSam BeardJoshua T BurgessLaura V CroftEmma BoldersonAli NaqiNicholas W AshtonMark Nathaniel AdamsKienan I SavageShu-Dong ZhangKenneth J O'ByrneDerek J RichardPublished in: Communications biology (2021)
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.
Keyphrases
- dna damage
- dna repair
- circulating tumor
- dna damage response
- oxidative stress
- gene expression
- cell free
- transcription factor
- induced apoptosis
- genome wide
- cell cycle arrest
- copy number
- crispr cas
- endothelial cells
- high resolution
- physical activity
- young adults
- machine learning
- electronic health record
- weight gain
- cell death
- dna methylation
- data analysis
- high glucose
- cell proliferation
- protein kinase
- artificial intelligence
- human health