COMMD4 functions with the histone H2A-H2B dimer for the timely repair of DNA double-strand breaks

Amila Suraweera, Neha S. Gandhi, Sam Beard, Joshua T. Burgess, Laura V. Croft, Emma Bolderson, Ali Naqi, Nicholas W. Ashton, Mark N. Adams, Kienan I. Savage, Shu-Dong Zhang, Kenneth J. O’Byrne, Derek J. Richard

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4 Citations (Scopus)
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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.
Original languageEnglish
Article number484
Pages (from-to)484
JournalCommunications Biology
Volume4
Issue number1
Early online date19 Apr 2021
DOIs
Publication statusPublished - 19 Apr 2021

Bibliographical note

Funding Information:
The authors wish to acknowledge all members of the Cancer and Ageing Research Program for helpful discussions regarding the findings of this paper. We would also like to thank Dr. Desi Veleva for technical assistance with experiments and the Translational Research Institute (TRI) for providing an excellent research environment and core facilities that enabled this research. We particularly would like to thank Ms. Yitian Ding from Flow Cytometry at TRI and Dr. Sandrine Roy from Microscopy at TRI. This work was supported by a Chenhall Research Award (D.J.R.), a Queensland Health Senior Clinical Research Fellowship (K.J.O.) and a generous Yancoal grant. N.W.A. was supported by a scholarship awarded by Cancer Council Queensland, N.S.G., J.T.B., L.V.C. and E.B. are supported by Advance Queensland Research Fellowships and M.N.A. is supported by an IHBI Strategic Research Fellowship.

Publisher Copyright:
© 2021, The Author(s).

Keywords

  • Adaptor Proteins, Signal Transducing/genetics
  • Biomarkers, Tumor/genetics
  • DNA Breaks, Double-Stranded
  • DNA Repair
  • HEK293 Cells
  • HeLa Cells
  • Histones/metabolism
  • Humans

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