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

Amila Suraweera; Neha Gandhi; Beard Sam; Burgess Joshua; Laura V. Croft; Emma Bolderson; Ali Naqi; Nicholas W. Ashton; Mark 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 Gandhi, Beard Sam , Burgess Joshua , Laura V. Croft, Emma Bolderson, Ali Naqi, Nicholas W. Ashton, Mark Adams, Kienan I. Savage, Shu‐Dong Zhang, Kenneth J O'Byrne, Derek J. Richard

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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 language	English
Article number	484
Number of pages	11
Journal	Communications Biology
Volume	4
DOIs	https://doi.org/10.1038/s42003-021-01998-2
Publication status	Published - 19 Apr 2021

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COMMD4 functions with the histone H2A-H2B dimer for the timely repair of DNA double-strand breaks
Copyright 2021 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 2.51 MBLicence: CC BY

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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.",

author = "Amila Suraweera and Neha Gandhi and Beard Sam and Burgess Joshua and Croft, {Laura V.} and Emma Bolderson and Ali Naqi and Ashton, {Nicholas W.} and Mark Adams and Savage, {Kienan I.} and Shu‐Dong Zhang and O'Byrne, {Kenneth J} and Richard, {Derek J.}",

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

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T1 - COMMD4 functions with the histone H2A-H2B dimer for the timely repair of DNA double-strand breaks

AU - Suraweera, Amila

AU - Gandhi, Neha

AU - Sam , Beard

AU - Joshua , Burgess

AU - Croft, Laura V.

AU - Bolderson, Emma

AU - Naqi, Ali

AU - Ashton, Nicholas W.

AU - Adams, Mark

AU - Savage, Kienan I.

AU - Zhang, Shu‐Dong

AU - O'Byrne, Kenneth J

AU - Richard, Derek J.

PY - 2021/4/19

Y1 - 2021/4/19

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.

AB - 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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DO - 10.1038/s42003-021-01998-2

M3 - Article

VL - 4

JO - Communications Biology

JF - Communications Biology

SN - 2399-3642

M1 - 484

ER -

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

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