What is it about?
CREBBP is one of the most commonly mutated genes in cancer. Broadly, mutations fall into two major categories: those that eliminate or truncate the protein through frameshifts or premature stop codons, or those that alter the activity of the intact protein through missense mutations in the catalytic lysine acetyltransferase (KAT) domain. We have previously shown that nonsense/frameshift mutations are functionally divergent from KAT domain point mutations, but the mechanism by which KAT domain mutations affect catalytic activity and whether there are differences between hotspots within the KAT domain is unknown. We find that the most frequent hotspot of CREBBP mutation (R1446) alters substrate binding and reduces catalytic activity, but retains detectable levels of acetyltransferase activity for a variety of substrates including histones and the p53 protein. In contrast, hotspot mutations in the catalytic core of CREBBP (Y1482 or Y1503) create a dead enzyme with no detectable activity, which has a greater impact on enhancer acetylation within CRISPR-engineered cells. CREBBP KAT domain mutations therefore fall into at least two sub-categories: those that destabilize substrate binding but retain some activity, and those that alter the catalytic core of the enzyme and are completely inactive.
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Why is it important?
In the post-genomic era, we are transitioning from discovering which genes are mutated to understanding the functional consequences of gene mutations. It is becoming clear that not all mutations in a given gene have the same functional consequence, which may affect how they are perceived in context of precision medicine efforts. This work gives detailed insight into the catalytic function of CREBBP, how it is deregulated by somatic mutations in cancer, how to interpret different classes of mutations through the lens of precision medicine.
Perspectives
CREBBP mutations became of interest to us because they reside within common progenitor cells of follicular lymphoma. In this respect, there is a preference for R1446 mutations in CREBBP that suggested there was something special about them. This work, together with other findings in the setting of lymphoma, confirm this suspicion. However, the R1446 hotspot is even more prominent in solid tumors and the mechanistic basis for deregulating (reducing but not eliminating) CREBBP activity in lung, colorectal and other solid tumors remains to be defined.
Michael Green
University of Texas MD Anderson Cancer Center
Read the Original
This page is a summary of: Structural and functional divergence of cancer hotspot mutations in CREBBP, Proceedings of the National Academy of Sciences, September 2026, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2605702123.
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