COMMD4 functions with the histone H2A-H2B dimer for the timely repair of DNA double-strand breaks
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Description
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.
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| ID Code: | 210226 | ||||||||||||||||
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| Item Type: | Contribution to Journal (Journal Article) | ||||||||||||||||
| Refereed: | Yes | ||||||||||||||||
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| Additional Information: | 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. | ||||||||||||||||
| Measurements or Duration: | 11 pages | ||||||||||||||||
| DOI: | 10.1038/s42003-021-01998-2 | ||||||||||||||||
| ISSN: | 2399-3642 | ||||||||||||||||
| Pure ID: | 83462268 | ||||||||||||||||
| Divisions: | Current > Research Centres > Centre for Genomics and Personalised Health Current > QUT Faculties and Divisions > Faculty of Science Current > Schools > School of Chemistry & Physics Current > QUT Faculties and Divisions > Faculty of Health Current > Schools > School of Biomedical Sciences |
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| 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. | ||||||||||||||||
| Copyright Owner: | 2021 The Author(s) | ||||||||||||||||
| Copyright Statement: | This work is covered by copyright. Unless the document is being made available under a Creative Commons Licence, you must assume that re-use is limited to personal use and that permission from the copyright owner must be obtained for all other uses. If the document is available under a Creative Commons License (or other specified license) then refer to the Licence for details of permitted re-use. It is a condition of access that users recognise and abide by the legal requirements associated with these rights. If you believe that this work infringes copyright please provide details by email to qut.copyright@qut.edu.au | ||||||||||||||||
| Deposited On: | 11 May 2021 02:29 | ||||||||||||||||
| Last Modified: | 22 Jun 2024 19:14 |
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