UBE2N

UBE2N, also known as UBC13, is a ubiquitin-conjugating enzyme E2 N that participates in non-proteolytic ubiquitination in human cells. It functions in concert with ubiquitin-conjugating enzyme variants UBE2V1 (MMS2) or UBE2V2 (MMS2-like), which are catalytically inactive and act as cofactors. The UBE2N-UBE2V1/UBE2V2 heterodimer promotes the formation of Lys63-linked polyubiquitin chains.

Lys63-linked ubiquitination, unlike Lys48-linked chains, regulates signaling rather than targeting proteins for degradation. The UBC13-UEV1/UEV2 complex is involved in several key pathways, including NF-kB activation in response to cytokines and DNA damage signaling. In the DNA damage response, it participates in PCNA ubiquitination to facilitate error-free post-replication repair and translesion synthesis. The complex is recruited by E3 ligases such as TRAF6 in signaling contexts and by RNF8/RNF168 in chromatin-related damage signaling.

UBE2N activity contributes to inflammatory and immune signaling and has implications in cancer and immune-related disorders when dysregulated. Its function in maintaining genomic stability through DNA damage tolerance underscores its importance in cell survival and homeostasis.

Structurally, UBE2N contains the conserved catalytic core with an active-site cysteine, enabling ubiquitin transfer. In contrast, UBE2V1 and UBE2V2 lack catalytic cysteine and serve as essential cofactors that guide the formation of Lys63-linked chains.

Therapeutically, disruption of the UBC13-UEV1/UEV2 interaction has been explored as a strategy to modulate signaling in cancer and inflammatory diseases.