Akano and Hebert et al. identify SMARCA3 as an E3 ligase for histone H3K23 ubiquitination, which stabilizes the repressive H3K9me3 mark. Frequently silenced in colorectal cancer, SMARCA3 regulates chromatin accessibility and the expression of cancer-associated genes, revealing a mechanistic link between histone ubiquitination and tumor suppression.

A cascade of three enzymes, E1−E2−E3, is responsible for transferring ubiquitin to target proteins, but the role of the central E2 has been largely overlooked. This work presents a new method, called...