P300 coactivator activity is altered by cancer mutations in the catalytic core

Abstract

The p300 protein is an important factor in gene expression due to its ability to acetylate histones and other proteins through its catalytic core domain, which is comprised of a bromodomain, RING-PHD domain, and histone acetyltransferase domain. p300 is often mutated in cancer cells, but the functional effects of many of these mutations have not been explored. In this project, the effects of p300 cancer mutations on coactivator activity and structure were investigated using structural and molecular approaches. Publicly available databases were used to initially identify all known p300 core point mutations observed in human tumors or associated with cancer. Structural models of the mutations were created to assess the root-mean-square-deviation induced by the residue changes. Using deactivated Cas9 fused to p300 core, the coactivator activity was compared across the mutations. We found that mutations in the histone acetyltransferase domain and RING domain significantly inhibited the coactivator activity of the core while bromodomain mutations had variable effects on coactivator activity. These results demonstrate that p300 core cancer mutations can alter p300 function and structure, suggesting that p300 mutations throughout the core may be perturbed in human tumors thereby contributing to the disease.