The bromodomain protein Brd4 insulates chromatin from DNA damage signalling

Scott R. Floyd; Michael E. Pacold; Qiuying Huang; Scott M. Clarke; Fred C. Lam; Ian G. Cannell; Bryan D. Bryson; Jonathan Rameseder; Michael J. Lee; Emily J. Blake; Anna Fydrych; Richard Ho; Benjamin A. Greenberger; Grace C. Chen; Amanda Maffa; Amanda M. Del Rosario; David E. Root; Anne E. Carpenter; William C. Hahn; David M. Sabatini; Clark C. Chen; Forest M. White; James E. Bradner; Michael B. Yaffe

doi:10.1038/nature12147

The bromodomain protein Brd4 insulates chromatin from DNA damage signalling

Scott R. Floyd, Michael E. Pacold, Qiuying Huang, Scott M. Clarke, Fred C. Lam, Ian G. Cannell, Bryan D. Bryson, Jonathan Rameseder, Michael J. Lee, Emily J. Blake, Anna Fydrych, Richard Ho, Benjamin A. Greenberger, Grace C. Chen, Amanda Maffa, Amanda M. Del Rosario, David E. Root, Anne E. Carpenter, William C. Hahn, David M. SabatiniClark C. Chen, Forest M. White, James E. Bradner, Michael B. Yaffe

Neurosurgery

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216 Scopus citations

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.

Original language	English (US)
Pages (from-to)	246-250
Number of pages	5
Journal	Nature
Volume	498
Issue number	7453
DOIs	https://doi.org/10.1038/nature12147
State	Published - 2013

Bibliographical note

Funding Information:
Acknowledgements We thank H. Le, T.R. Jones and M. Vokes for assistance with screening and image analysis. We thank C. Whittaker, S. Hoersch and M. Moran for computing and data analysis assistance; C. Reinhardt, C. Ellson and A. Gardino for manuscript editing; and P. Filippakopoulos and S. Knapp for discussions. This work was partially supported by the Koch Institute and Center for Environmental Health Sciences National Institutes of Health Core Grants P30-CA14051 and ES-002109; and by grants R01-ES15339, 1-U54-CA112967-04 and R21-NS063917; a SPARC grant to M.B.Y.; and a Holman Pathway Research Resident Seed Grant, American Society for Radiation Oncology Junior Faculty Career Research Training Award, Klarman Scholar, Koch Institute Clinical Investigator Award, and Burroughs Wellcome Career Award for Medical Scientists to S.R.F.

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Floyd, S. R., Pacold, M. E., Huang, Q., Clarke, S. M., Lam, F. C., Cannell, I. G., Bryson, B. D., Rameseder, J., Lee, M. J., Blake, E. J., Fydrych, A., Ho, R., Greenberger, B. A., Chen, G. C., Maffa, A., Del Rosario, A. M., Root, D. E., Carpenter, A. E., Hahn, W. C., ... Yaffe, M. B. (2013). The bromodomain protein Brd4 insulates chromatin from DNA damage signalling. Nature, 498(7453), 246-250. https://doi.org/10.1038/nature12147

Floyd, SR, Pacold, ME, Huang, Q, Clarke, SM, Lam, FC, Cannell, IG, Bryson, BD, Rameseder, J, Lee, MJ, Blake, EJ, Fydrych, A, Ho, R, Greenberger, BA, Chen, GC, Maffa, A, Del Rosario, AM, Root, DE, Carpenter, AE, Hahn, WC, Sabatini, DM, Chen, CC, White, FM, Bradner, JE & Yaffe, MB 2013, 'The bromodomain protein Brd4 insulates chromatin from DNA damage signalling', Nature, vol. 498, no. 7453, pp. 246-250. https://doi.org/10.1038/nature12147

@article{ad2ec57b3b534721bfcbe73cbdbf2e6a,

title = "The bromodomain protein Brd4 insulates chromatin from DNA damage signalling",

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.",

author = "Floyd, {Scott R.} and Pacold, {Michael E.} and Qiuying Huang and Clarke, {Scott M.} and Lam, {Fred C.} and Cannell, {Ian G.} and Bryson, {Bryan D.} and Jonathan Rameseder and Lee, {Michael J.} and Blake, {Emily J.} and Anna Fydrych and Richard Ho and Greenberger, {Benjamin A.} and Chen, {Grace C.} and Amanda Maffa and {Del Rosario}, {Amanda M.} and Root, {David E.} and Carpenter, {Anne E.} and Hahn, {William C.} and Sabatini, {David M.} and Chen, {Clark C.} and White, {Forest M.} and Bradner, {James E.} and Yaffe, {Michael B.}",

note = "Funding Information: Acknowledgements We thank H. Le, T.R. Jones and M. Vokes for assistance with screening and image analysis. We thank C. Whittaker, S. Hoersch and M. Moran for computing and data analysis assistance; C. Reinhardt, C. Ellson and A. Gardino for manuscript editing; and P. Filippakopoulos and S. Knapp for discussions. This work was partially supported by the Koch Institute and Center for Environmental Health Sciences National Institutes of Health Core Grants P30-CA14051 and ES-002109; and by grants R01-ES15339, 1-U54-CA112967-04 and R21-NS063917; a SPARC grant to M.B.Y.; and a Holman Pathway Research Resident Seed Grant, American Society for Radiation Oncology Junior Faculty Career Research Training Award, Klarman Scholar, Koch Institute Clinical Investigator Award, and Burroughs Wellcome Career Award for Medical Scientists to S.R.F.",

year = "2013",

doi = "10.1038/nature12147",

language = "English (US)",

volume = "498",

pages = "246--250",

journal = "Nature",

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TY - JOUR

T1 - The bromodomain protein Brd4 insulates chromatin from DNA damage signalling

AU - Floyd, Scott R.

AU - Pacold, Michael E.

AU - Huang, Qiuying

AU - Clarke, Scott M.

AU - Lam, Fred C.

AU - Cannell, Ian G.

AU - Bryson, Bryan D.

AU - Rameseder, Jonathan

AU - Lee, Michael J.

AU - Blake, Emily J.

AU - Fydrych, Anna

AU - Ho, Richard

AU - Greenberger, Benjamin A.

AU - Chen, Grace C.

AU - Maffa, Amanda

AU - Del Rosario, Amanda M.

AU - Root, David E.

AU - Carpenter, Anne E.

AU - Hahn, William C.

AU - Sabatini, David M.

AU - Chen, Clark C.

AU - White, Forest M.

AU - Bradner, James E.

AU - Yaffe, Michael B.

N1 - Funding Information: Acknowledgements We thank H. Le, T.R. Jones and M. Vokes for assistance with screening and image analysis. We thank C. Whittaker, S. Hoersch and M. Moran for computing and data analysis assistance; C. Reinhardt, C. Ellson and A. Gardino for manuscript editing; and P. Filippakopoulos and S. Knapp for discussions. This work was partially supported by the Koch Institute and Center for Environmental Health Sciences National Institutes of Health Core Grants P30-CA14051 and ES-002109; and by grants R01-ES15339, 1-U54-CA112967-04 and R21-NS063917; a SPARC grant to M.B.Y.; and a Holman Pathway Research Resident Seed Grant, American Society for Radiation Oncology Junior Faculty Career Research Training Award, Klarman Scholar, Koch Institute Clinical Investigator Award, and Burroughs Wellcome Career Award for Medical Scientists to S.R.F.

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

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DO - 10.1038/nature12147

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EP - 250

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7453

ER -

The bromodomain protein Brd4 insulates chromatin from DNA damage signalling

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