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
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: | 21 Dec 2023 15:27 |
| PMCID: | PMC6222455 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/37122 |
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