E2-E3 ubiquitin enzyme pairing-partnership in provoking or mitigating cancers

The ubiquitin-proteasome system (UPS) modulates carcinogenesis through ubiquitination of cancer-related target proteins, leading to their degradation in the proteasome. This may deactivate tumor suppressors or activate tumor promoters-either way causing homeostatic imbalance. As major components of the UPS, the E2 and E3 enzymes are recognized as pivotal determinants of substrate recognition and ubiquitination. Identification of E2-E3 pairing selectivity is particularly pertinent to early diagnosis and potential development of targeted cancer therapeutics. This review is motivated by recent findings and new insights into the molecular dynamics of ubiquitination triggered by specific E2-E3 pairing, leading to cancer initiation and progression if cancer suppressors are degraded or cancer suppression (if cancer promoters are degraded), respectively. We provide an overview of strategies employed in screening for E2-E3 interactions based on up-to-date studies focusing on the E2-E3 interface motifs. Of considerable recent interest is how E2 and E3 might switch their functional partnerships via UBE2O, which suggests an emerging significance on how UBE2O might influence E2-E3 pairing. Thus, a reflection on the role of UBE2O is included. Finally, we deliberate on the rational and cautious development of anti-cancer cocktail drugs which specifically target E2-E3 interacting residues for precision in cancer killing with minimal side-effects. To this end, a list of potential future research is proposed.

Automated summary

The ubiquitin-proteasome system plays a crucial role in modulating carcinogenesis by ubiquitination of cancer-related target proteins. Specific E2-E3 pairings are key in cancer progression, and current research focuses on E2-E3 interface motifs and the influence of UBE2O on E2-E3 pairing. The development of anti-cancer drugs targeting E2-E3 interacting residues for precision in cancer treatment is being carefully considered.