The bromodomain protein Brd4 insulates chromatin from DNA damage signalling

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

doi:10.1038/nature12147

Cited by 287 publications

(286 citation statements)

References 22 publications

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“…BRD proteins are the primary readers of acetylated chromatin, and several studies as well as our data reported here suggest the importance of this protein family in the DDR (Park et al 2006;Lan et al 2010;Ogiwara et al 2011;Lee et al 2012;Floyd et al 2013;Kulkarni et al 2013). Our screen identified damage-associated BRD proteins representing four general classes of proteins: (1) HATs, (2) chromatin remodelers, (3) TRIM proteins, and (4) ZMYND8.…”

Section: Brd Proteins As Mediators Of the Ddrmentioning

confidence: 98%

“…There are 42 human BRD-containing proteins (Filippakopoulos et al 2012). Generally classified as transcriptional regulators, several BRD proteins (e.g., p300, TRIM28, BAZ1B, and BRD4) are involved in the DDR (Barnett and Krebs 2011;Iyengar and Farnham 2011;Ogiwara et al 2011;Floyd et al 2013). BRD proteins are potential candidates for reading DDR-specific acetylation changes occurring at DNA damage sites.…”

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confidence: 99%

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Screen identifies bromodomain protein ZMYND8 in chromatin recognition of transcription-associated DNA damage that promotes homologous recombination

et al. 2015

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How chromatin shapes pathways that promote genome-epigenome integrity in response to DNA damage is an issue of crucial importance. We report that human bromodomain (BRD)-containing proteins, the primary ''readers'' of acetylated chromatin, are vital for the DNA damage response (DDR). We discovered that more than one-third of all human BRD proteins change localization in response to DNA damage. We identified ZMYND8 (zinc finger and MYND [myeloid, Nervy, and DEAF-1] domain containing 8) as a novel DDR factor that recruits the nucleosome remodeling and histone deacetylation (NuRD) complex to damaged chromatin. Our data define a transcription-associated DDR pathway mediated by ZMYND8 and the NuRD complex that targets DNA damage, including when it occurs within transcriptionally active chromatin, to repress transcription and promote repair by homologous recombination. Thus, our data identify human BRD proteins as key chromatin modulators of the DDR and provide novel insights into how DNA damage within actively transcribed regions requires chromatin-binding proteins to orchestrate the appropriate response in concordance with the damage-associated chromatin context.

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Section: Brd Proteins As Mediators Of the Ddrmentioning

confidence: 98%

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confidence: 99%

Screen identifies bromodomain protein ZMYND8 in chromatin recognition of transcription-associated DNA damage that promotes homologous recombination

et al. 2015

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“…A short isoform of BRD4 was recently shown to be an inhibitor of DNA damage response signaling by influencing chromatin structure independently of its role as a transcriptional activator (44). Resistance to BETi could thus theoretically arise by reduction of DNA damage signaling, bypassing growth arrest.…”

Section: Discussionmentioning

confidence: 99%

Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β–dependent mechanisms

Shi

Mihaylova

Kuruvilla

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Bromodomain and extraterminal domain protein inhibitors (BETi) hold great promise as a novel class of cancer therapeutics. Because acquired resistance typically limits durable responses to targeted therapies, it is important to understand mechanisms by which tumor cells adapt to BETi. Here, through pooled shRNA screening of colorectal cancer cells, we identified tripartite motif-containing protein 33 (TRIM33) as a factor promoting sensitivity to BETi. We demonstrate that loss of TRIM33 reprograms cancer cells to a more resistant state through at least two mechanisms. TRIM33 silencing attenuates down-regulation of MYC in response to BETi. Moreover, loss of TRIM33 enhances TGF-β receptor expression and signaling, and blocking TGF-β receptor activity potentiates the antiproliferative effect of BETi. These results describe a mechanism for BETi resistance and suggest that combining inhibition of TGF-β signaling with BET bromodomain inhibition may offer new therapeutic benefits.bromodomain inhibitor | TRIM33 | JQ1 | drug resistance | TGF-β

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“…Chromatin compaction is another important impediment of the DDR. Histone deacetylases (Murga et al, 2007) and the condensin II chromatin remodelling complex recruiter BRD4 (Floyd et al, 2013) promotes chromatin compaction and restrict spreading of DDR signalling on chromatin. Finally, after repair has taken place the histone chaperones Asf1, Caf1 and HIRA are required for restoring nucleosomes at the site of damage.…”

Section: Removal Of Modified Proteinsmentioning

confidence: 99%

The same, only different – DNA damage checkpoints and their reversal throughout the cell cycle

Shaltiël

Krenning

Bruinsma

et al. 2015

Journal of Cell Science

254

272

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Cell cycle checkpoints activated by DNA double-strand breaks (DSBs) are essential for the maintenance of the genomic integrity of proliferating cells. Following DNA damage, cells must detect the break and either transiently block cell cycle progression, to allow time for repair, or exit the cell cycle. Reversal of a DNA-damageinduced checkpoint not only requires the repair of these lesions, but a cell must also prevent permanent exit from the cell cycle and actively terminate checkpoint signalling to allow cell cycle progression to resume. It is becoming increasingly clear that despite the shared mechanisms of DNA damage detection throughout the cell cycle, the checkpoint and its reversal are precisely tuned to each cell cycle phase. Furthermore, recent findings challenge the dogmatic view that complete repair is a precondition for cell cycle resumption. In this Commentary, we highlight cell-cycle-dependent differences in checkpoint signalling and recovery after a DNA DSB, and summarise the molecular mechanisms that underlie the reversal of DNA damage checkpoints, before discussing when and how cell fate decisions after a DSB are made.

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The bromodomain protein Brd4 insulates chromatin from DNA damage signalling

Cited by 287 publications

References 22 publications

Screen identifies bromodomain protein ZMYND8 in chromatin recognition of transcription-associated DNA damage that promotes homologous recombination

Screen identifies bromodomain protein ZMYND8 in chromatin recognition of transcription-associated DNA damage that promotes homologous recombination

Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β–dependent mechanisms

The same, only different – DNA damage checkpoints and their reversal throughout the cell cycle

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