Structural and functional divergence of cancer hotspot mutations in CREBBP.

Recurrent mutations in CREBBP's KAT domain cause functionally divergent effects, with some preserving activity and others leading to loss of acetyltransferase function.

• Why it matters: Understanding how specific mutations impact CREBBP's function is crucial because it is a frequently mutated gene in human cancer, influencing transcription regulation and tumor progression.
• What they did: The study analyzed 3D structures and biochemical properties of common CREBBP mutations, focusing on arginine 1446 and other residues within the KAT domain, to assess their effects on enzyme activity.
• The result: Mutations like R1446 alter cofactor binding stability but retain some activity, while others disrupt the catalytic center, causing a loss of histone acetylation and enhancer function, revealing distinct mutation classes.