E2 enzymes in genome stability: pulling the strings behind the scenes

Ubiquitin and ubiquitin-like proteins (UBLs) function as critical post-translational modifiers in the maintenance of genome stability. Ubiquitin/UBL-conjugating enzymes (E2s) are responsible, as part of a wider enzymatic cascade, for transferring single moieties or polychains of ubiquitin/UBLs to one or multiple residues on substrate proteins. Recent advances in structural and mechanistic understanding of how ubiquitin/UBL substrate attachment is orchestrated indicate that E2s can exert control over chain topology, substrate-site specificity, and downstream physiological effects to help maintain genome stability. Drug discovery efforts have typically focussed on modulating other members of the ubiquitin/UBL cascades or the ubiquitin-proteasome system. Here, we review the current standing of E2s in genome stability and revisit their potential as pharmacological targets for developing novel anti-cancer therapies.

Automated summary

Ubiquitin and ubiquitin-like proteins play critical roles in maintaining genome stability, with E2 enzymes responsible for transferring these proteins to substrate proteins. Recent studies have shown that E2 enzymes can control chain topology and substrate-site specificity, making them potential targets for developing novel anti-cancer therapies.