A bromodomain–DNA interaction facilitates acetylation-dependent bivalent nucleosome recognition by the BET protein BRDT

Thomas C. R. Miller, Bernd Simon, Vladimir Rybin, Helga Grötsch, Sandrine Curtet, Saadi Khochbin, Teresa Carlomagno () and Christoph W. Müller ()
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Thomas C. R. Miller: European Molecular Biology Laboratory (EMBL), Structural and Computational Biology Unit
Bernd Simon: European Molecular Biology Laboratory (EMBL), Structural and Computational Biology Unit
Vladimir Rybin: European Molecular Biology Laboratory (EMBL), Structural and Computational Biology Unit
Helga Grötsch: European Molecular Biology Laboratory (EMBL), Structural and Computational Biology Unit
Sandrine Curtet: CNRS UMR 5309, INSERM, U1209, Université Grenoble Alpes, Institut Albert Bonniot
Saadi Khochbin: CNRS UMR 5309, INSERM, U1209, Université Grenoble Alpes, Institut Albert Bonniot
Teresa Carlomagno: European Molecular Biology Laboratory (EMBL), Structural and Computational Biology Unit
Christoph W. Müller: European Molecular Biology Laboratory (EMBL), Structural and Computational Biology Unit

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract Bromodomains are critical components of many chromatin modifying/remodelling proteins and are emerging therapeutic targets, yet how they interact with nucleosomes, rather than acetylated peptides, remains unclear. Using BRDT as a model, we characterized how the BET family of bromodomains interacts with site-specifically acetylated nucleosomes. Here we report that BRDT interacts with nucleosomes through its first (BD1), but not second (BD2) bromodomain, and that acetylated histone recognition by BD1 is complemented by a bromodomain–DNA interaction. Simultaneous DNA and histone recognition enhances BRDT’s nucleosome binding affinity and specificity, and its ability to localize to acetylated chromatin in cells. Conservation of DNA binding in bromodomains of BRD2, BRD3 and BRD4, indicates that bivalent nucleosome recognition is a key feature of these bromodomains and possibly others. Our results elucidate the molecular mechanism of BRDT association with nucleosomes and identify structural features of the BET bromodomains that may be targeted for therapeutic inhibition.

Date: 2016
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DOI: 10.1038/ncomms13855

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