Abstract
Histone acetyltransferase coactivators bind to acetylated histones through their bromodomains and catalyze the acetylation of histone H3 and H4 tails for transcriptional activation. C-terminal binding protein (CtBP) serves as a transcriptional corepressor by recruiting histone deacetylases. However, the precise mechanism by which CtBP represses transcription has not been determined. In this study we found that CtBP1 directly associates with p300 by binding to the PXDLS motif in the bromodomain of p300. Moreover, CtBP1 blocks the accessibility of p300 to histones in an NADH-sensitive manner and thus represses p300-mediated histone acetylation and transcriptional activation. In addition, an NADH-nonresponsive, monomeric mutant, CtBP1 (G183V), was found to strongly repress p300-mediated transcriptional activation. Thus, the dissociation of NADH from CtBP1 leads to the repression of p300-driven general transcriptional activity by CtBP1. These results suggest a novel mechanism whereby CtBP1 serves as an energy-sensing repressor of histone acetyltransferase(s) and thus affects general transcription.
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Acknowledgements
We thank J.O. Liu (Johns Hopkins School of Medicine) for critical reading of the manuscript; G. Chinnadurai (Saint Louis University) for pGEX-CtBP1 and pcDNA3-E1A plasmids; and J.D. Hildebrand (University of Pittsburgh) for ctbp(−/−) and ctbp(+/−) MEF cells. This work was supported by Research for Pure Basic Science, Korea Research Foundation (2002-KRF-C00070, to H.-D.Y.), and in part by Korea Science & Engineering Foundation (KOSEF) through the Center for Aging and Apoptosis Research at Seoul National University.
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Supplementary information
Supplementary Fig. 1
The alignment of putative CtBP1-binding motifs among bromodomain-containing proteins. (PDF 139 kb)
Supplementary Fig. 2
The D1098A L1099A mutant of full-length p300 works as a dominant negative competitor of VP16-mediated transactivation. (PDF 340 kb)
Supplementary Fig. 3
NADH-nonresponsive mutants of CtBP1 bind to p300 more stably. (PDF 373 kb)
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Kim, JH., Cho, EJ., Kim, ST. et al. CtBP represses p300-mediated transcriptional activation by direct association with its bromodomain. Nat Struct Mol Biol 12, 423–428 (2005). https://doi.org/10.1038/nsmb924
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DOI: https://doi.org/10.1038/nsmb924
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