Year: 2026
Type: article
Abstract: CREBBP is among the most frequently mutated genes in human cancer and encodes a lysine acetyltransferase (KAT) protein that acetylates histones and nonhistone proteins to drive transcriptional activation. Mutations of CREBBP most frequently result in missense changes affecting the active site within the KAT domain. However, there has not yet been comprehensive biochemical, structural, and functional studies to determine the impact of recurrent KAT-domain variants. Here we show that the most frequently mutated residue of CREBBP , arginine 1446, alters the stability of acetyl-CoA binding within the cofactor-binding pocket but retains detectable acetyltransferase activity for a variety of substrates including histones. In contrast, other recurrently mutated residues affect the catalytic center within the KAT domain and result in a catalytically dead protein with a profound loss of histone acetylation and enhancer activity. These results highlight functionally divergent classes of CREBBP mutations depending on the position of the mutated residue within KAT domain.
Authors: Wenchao Zhang, Haopeng Yang, Ariel Mechaly, Zhongyang Li, Guiling Cui, Leslie Regad, Romain Duval, Julien Dairou, Ahmed Haouz, Michael R. Green, Fernando Rodrigues Lima
Institutions: The University of Texas MD Anderson Cancer Center, Centre National de la Recherche Scientifique, Institut Pasteur, Université Paris Cité, Biologie Moléculaire Structurale et Processus Infectieux, Unit of Functional and Adaptive Biology, Inserm, Établissement Français du Sang, Biologie intégrée du globule rouge et de l'Erythropoïèse, Université des Antilles, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Funder: National Cancer Institute
OpenAlex ID: W7214057403