COMMD4 与组蛋白 H2A-H2B 二聚体一起作用，以实现 DNA 双链断裂的及时修复。
COMMD4 functions with the histone H2A-H2B dimer for the timely repair of DNA double-strand breaks.
机构信息
Queensland University of Technology (QUT), School of Biomedical Sciences, Centre for Genomics and Personalised Health at the Translational Research Institute, Woolloongabba, QLD, Australia.
Queensland University of Technology (QUT), School of Chemistry and Physics, Faculty of Science and Engineering, Centre for Genomics and Personalised Health, Brisbane, QLD, Australia.
出版信息
Commun Biol. 2021 Apr 19;4(1):484. doi: 10.1038/s42003-021-01998-2.
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.
基因组稳定性对于正常细胞功能至关重要，其失调是癌症的普遍标志。在这里，我们概述了 COMMD4 通过调节 DNA 双链断裂部位的染色质重塑来维持基因组稳定性的先前未描述的作用。在断裂部位，COMMD4 与组蛋白 H2B 结合，并防止 RNF20/RNF40 将其单泛素化。DNA 损伤诱导的 H2A-H2B 异二聚体磷酸化破坏了二聚体，使 COMMD4 能够优先结合 H2A。COMMD4 从 H2B 上的置换允许 RNF20/40 对 H2B 进行单泛素化，并使断裂部位发生重塑。与这一关键功能一致，COMMD4 缺陷细胞显示出重塑染色质的过度伸长，以及非同源末端连接和同源重组的失败。我们提出了用于指导 COMMD4 在 DNA 双链断裂处介导染色质调节的潜在分子机制的肽图谱和突变分析数据。
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