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

doi:10.1038/s42003-021-01998-2

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

Queensland University of Technology

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

296 Downloads (Pure)

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 language	English
Article number	484
Pages (from-to)	484
Journal	Communications Biology
Volume	4
Issue number	1
Early online date	19 Apr 2021
DOIs	https://doi.org/10.1038/s42003-021-01998-2
Publication status	Published (in print/issue) - 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).

Funding

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).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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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10.1038/s42003-021-01998-2Licence: CC BY

Final published versionFinal published version, 2.51 MBLicence: CC BY
Supplementary informationFinal published version, 10.7 MBLicence: CC BY

Cite this

Suraweera, A., Gandhi, N. S., Beard, S., Burgess, J. T., Croft, L. V., Bolderson, E., Naqi, A., Ashton, N. W., Adams, M. N., Savage, K. I., Zhang, S.-D., O’Byrne, K. J., & Richard, D. J. (2021). COMMD4 functions with the histone H2A-H2B dimer for the timely repair of DNA double-strand breaks. Communications Biology, 4(1), 484. Article 484. https://doi.org/10.1038/s42003-021-01998-2

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title = "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-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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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: {\textcopyright} 2021, The Author(s).",

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doi = "10.1038/s42003-021-01998-2",

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AU - Beard, Sam

AU - Burgess, Joshua T.

AU - Croft, Laura V.

AU - Bolderson, Emma

AU - Naqi, Ali

AU - Ashton, Nicholas W.

AU - Adams, Mark N.

AU - Savage, Kienan I.

AU - Zhang, Shu-Dong

AU - O’Byrne, Kenneth J.

AU - Richard, Derek J.

N1 - 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).

PY - 2021/4/19

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N2 - 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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KW - Adaptor Proteins, Signal Transducing/genetics

KW - Biomarkers, Tumor/genetics

KW - DNA Breaks, Double-Stranded

KW - DNA Repair

KW - HEK293 Cells

KW - HeLa Cells

KW - Histones/metabolism

KW - Humans

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DO - 10.1038/s42003-021-01998-2

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SN - 2399-3642

VL - 4

SP - 484

JO - Communications Biology

JF - Communications Biology

IS - 1

M1 - 484

ER -

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

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

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