The bromodomain protein Brd4 insulates chromatin from DNA damage signalling.

dc.contributor.author

Floyd, Scott R

dc.contributor.author

Pacold, Michael E

dc.contributor.author

Huang, Qiuying

dc.contributor.author

Clarke, Scott M

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Lam, Fred C

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Cannell, Ian G

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Bryson, Bryan D

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Rameseder, Jonathan

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Lee, Michael J

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Blake, Emily J

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Fydrych, Anna

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Ho, Richard

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Greenberger, Benjamin A

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Chen, Grace C

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Maffa, Amanda

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Del Rosario, Amanda M

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Root, David E

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Carpenter, Anne E

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Hahn, William C

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Sabatini, David M

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Chen, Clark C

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White, Forest M

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Bradner, James E

dc.contributor.author

Yaffe, Michael B

dc.coverage.spatial

England

dc.date.accessioned

2018-01-01T18:22:50Z

dc.date.available

2018-01-01T18:22:50Z

dc.date.issued

2013-06-13

dc.description.abstract

DNA damage activates a signalling network that blocks cell-cycle progression, recruits DNA repair factors and/or triggers senescence or programmed cell death. Alterations in chromatin structure are implicated in the initiation and propagation of the DNA damage response. Here we further investigate the role of chromatin structure in the DNA damage response by monitoring ionizing-radiation-induced signalling and response events with a high-content multiplex RNA-mediated interference screen of chromatin-modifying and -interacting genes. We discover that an isoform of Brd4, a bromodomain and extra-terminal (BET) family member, functions as an endogenous inhibitor of DNA damage response signalling by recruiting the condensin II chromatin remodelling complex to acetylated histones through bromodomain interactions. Loss of this isoform results in relaxed chromatin structure, rapid cell-cycle checkpoint recovery and enhanced survival after irradiation, whereas functional gain of this isoform compacted chromatin, attenuated DNA damage response signalling and enhanced radiation-induced lethality. These data implicate Brd4, previously known for its role in transcriptional control, as an insulator of chromatin that can modulate the signalling response to DNA damage.

dc.identifier

https://www.ncbi.nlm.nih.gov/pubmed/23728299

dc.identifier

nature12147

dc.identifier.eissn

1476-4687

dc.identifier.uri

https://hdl.handle.net/10161/15937

dc.language

eng

dc.publisher

Springer Science and Business Media LLC

dc.relation.ispartof

Nature

dc.relation.isversionof

10.1038/nature12147

dc.subject

Acetylation

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Adenosine Triphosphatases

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Cell Cycle Checkpoints

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Cell Line, Tumor

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Cell Survival

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Chromatin

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Chromatin Assembly and Disassembly

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DNA Damage

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DNA Repair

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DNA-Binding Proteins

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Histones

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Humans

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Lysine

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Multiprotein Complexes

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Nuclear Proteins

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Phosphorylation

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Positive Transcriptional Elongation Factor B

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Protein Isoforms

dc.subject

Radiation, Ionizing

dc.subject

Signal Transduction

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Transcription Factors

dc.title

The bromodomain protein Brd4 insulates chromatin from DNA damage signalling.

dc.type

Journal article

pubs.author-url

https://www.ncbi.nlm.nih.gov/pubmed/23728299

pubs.begin-page

246

pubs.end-page

250

pubs.issue

7453

pubs.organisational-group

Basic Science Departments

pubs.organisational-group

Clinical Science Departments

pubs.organisational-group

Duke

pubs.organisational-group

Duke Cancer Institute

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Institutes and Centers

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Pharmacology & Cancer Biology

pubs.organisational-group

Radiation Oncology

pubs.organisational-group

School of Medicine

pubs.organisational-group

Temp group - logins allowed

pubs.publication-status

Published

pubs.volume

498

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