Chemical strategies for trapping fleeting enzymatic complexes in nucleosome ubiquitylation

Site-specific ubiquitylation of nucleosomal histones, catalyzed by E3 ubiquitin ligase, plays a pivotal role in chromatin-templated processes, including transcriptional activation, gene silencing, and DNA damage repair. However, the inherently transient and dynamic interactions between the ubiquitin enzymes and the nucleosome substrate during the ubiquitylation cascade pose significant challenges to stabilizing functional complexes for structural and biochemical interrogation, thereby impeding mechanistic dissection. Recent advances in chemical biology strategies have emerged as powerful tools for resolving ternary ubiquitylation complexes of E3 ligase, E2∼Ub, and substrate. In this review, we systematically survey these innovative chemical approaches for trapping labile nucleosome ubiquitylation intermediates and consolidate the mechanistic insights into chromatin ubiquitylation biology.