Inhibitor of CBP Histone Acetyltransferase Downregulates p53 Activation and Facilitates Methylation at Lysine 27 on Histone H3

Vincek, A. S., Patel, J., Jaganathan, A., Green, A., Pierre-Louis, V., Arora, V., Rehmann, J., Mezei, M., Zhou, M. M., Ohlmeyer, M., Mujtaba, S. (August 2018) Inhibitor of CBP Histone Acetyltransferase Downregulates p53 Activation and Facilitates Methylation at Lysine 27 on Histone H3. Molecules, 23 (8). ISSN 1420-3049

URL: https://www.ncbi.nlm.nih.gov/pubmed/30072621
DOI: 10.3390/molecules23081930

Abstract

Tumor suppressor p53-directed apoptosis triggers loss of normal cells, which contributes to the side-effects from anticancer therapies. Thus, small molecules with potential to downregulate the activation of p53 could minimize pathology emerging from anticancer therapies. Acetylation of p53 by the histone acetyltransferase (HAT) domain is the hallmark of coactivator CREB-binding protein (CBP) epigenetic function. During genotoxic stress, CBP HAT-mediated acetylation is essential for the activation of p53 to transcriptionally govern target genes, which control cellular responses. Here, we present a small molecule, NiCur, which blocks CBP HAT activity and downregulates p53 activation upon genotoxic stress. Computational modeling reveals that NiCur docks into the active site of CBP HAT. On CDKN1A promoter, the recruitment of p53 as well as RNA Polymerase II and levels of acetylation on histone H3 were diminished by NiCur. Specifically, NiCur reduces the levels of acetylation at lysine 27 on histone H3, which concomitantly increases the levels of trimethylation at lysine 27. Finally, NiCur attenuates p53-directed apoptosis by inhibiting the Caspase 3 activity and cleavage of Poly (ADP-ribose) polymerase (PARP) in normal gastrointestinal epithelial cells. Collectively, NiCur demonstrates the potential to reprogram the chromatin landscape and modulate biological outcomes of CBP-mediated acetylation under normal and disease conditions.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > histone
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein methylation > histone methylation
CSHL Authors:
Depositing User: Matthew Dunn
Date: 2 August 2018
Date Deposited: 14 Aug 2018 16:01
Last Modified: 14 Aug 2018 16:01
Related URLs:
URI: http://repository.cshl.edu/id/eprint/37122

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