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COMMD4 Functions with the Histone H2A-H2B Dimer for the Timely Repair of DNA Double Strand Breaks

60 Pages Posted: 10 Jan 2020 Sneak Peek Status: Under Review

See all articles by Amila Suraweera

Amila Suraweera

Queensland University of Technology - School of Biomedical Sciences

Neha Gandhi

Queensland University of Technology - School of Mathematical Sciences

Sam Beard

Queensland University of Technology - School of Biomedical Sciences

Joshua Burgess

Queensland University of Technology - School of Biomedical Sciences

Ali Naqi

Queensland University of Technology - School of Biomedical Sciences

Emma Bolderson

Queensland University of Technology - School of Biomedical Sciences

Laura Croft

Queensland University of Technology - School of Biomedical Sciences

Nicholas Ashton

Queensland University of Technology - School of Biomedical Sciences

Mark N. Adams

Queensland University of Technology - School of Biomedical Sciences

Kienan Savage

Queen's University Belfast - Centre for Cancer Research and Cell Biology

Shu-Dong Zhang

Ulster University - Northern Ireland Centre for Stratified Medicine

Kenneth O'Byrne

Queensland University of Technology - School of Biomedical Sciences

Derek Richard

Queensland University of Technology - School of Biomedical Sciences

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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 regulating of chromatin remodelling at sites of DNA double strand breaks (DSBs). We demonstrate that COMMD4 is initially recruited to DSBs by a direct-interaction with phosphorylated hSSB1. 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 monoubuquitinate H2B and for remodelling of the break-site. Consistent with this critical function, COMMD4-defficient cells show excessive elongation of remodelled chromatin and failure of both non-homologous-end-joining and homologous recombination. We present a model, developed by molecular dynamic simulation, peptide-mapping and mutagenesis for the potential molecular mechanisms governing COMMD4-mediated chromatin regulation at DSBs.

Keywords: H2A, H2B, H2A-H2B dimer, DNA double strand breaks, genomic stability, COMMD4

Suggested Citation

Suraweera, Amila and Gandhi, Neha and Beard, Sam and Burgess, Joshua and Naqi, Ali and Bolderson, Emma and Croft, Laura and Ashton, Nicholas and Adams, Mark N. and Savage, Kienan and Zhang, Shu-Dong and O'Byrne, Kenneth and Richard, Derek, COMMD4 Functions with the Histone H2A-H2B Dimer for the Timely Repair of DNA Double Strand Breaks. CELL-REPORTS-D-19-05169. Available at SSRN: https://ssrn.com/abstract=3516893 or http://dx.doi.org/10.2139/ssrn.3516893
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Amila Suraweera (Contact Author)

Queensland University of Technology - School of Biomedical Sciences ( email )

60 Musk Avenue
Kelvin Grove
Brisbane, Queensland 4059
Australia

Neha Gandhi

Queensland University of Technology - School of Mathematical Sciences

Brisbane
Australia

Sam Beard

Queensland University of Technology - School of Biomedical Sciences

60 Musk Avenue
Kelvin Grove
Brisbane, Queensland 4059
Australia

Joshua Burgess

Queensland University of Technology - School of Biomedical Sciences

60 Musk Avenue
Kelvin Grove
Brisbane, Queensland 4059
Australia

Ali Naqi

Queensland University of Technology - School of Biomedical Sciences

60 Musk Avenue
Kelvin Grove
Brisbane, Queensland 4059
Australia

Emma Bolderson

Queensland University of Technology - School of Biomedical Sciences

60 Musk Avenue
Kelvin Grove
Brisbane, Queensland 4059
Australia

Laura Croft

Queensland University of Technology - School of Biomedical Sciences

60 Musk Avenue
Kelvin Grove
Brisbane, Queensland 4059
Australia

Nicholas Ashton

Queensland University of Technology - School of Biomedical Sciences

60 Musk Avenue
Kelvin Grove
Brisbane, Queensland 4059
Australia

Mark N. Adams

Queensland University of Technology - School of Biomedical Sciences

60 Musk Avenue
Kelvin Grove
Brisbane, Queensland 4059
Australia

Kienan Savage

Queen's University Belfast - Centre for Cancer Research and Cell Biology

Belfast
Ireland

Shu-Dong Zhang

Ulster University - Northern Ireland Centre for Stratified Medicine

United Kingdom

Kenneth O'Byrne

Queensland University of Technology - School of Biomedical Sciences

60 Musk Avenue
Kelvin Grove
Brisbane, Queensland 4059
Australia

Derek Richard

Queensland University of Technology - School of Biomedical Sciences

60 Musk Avenue
Kelvin Grove
Brisbane, Queensland 4059
Australia

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