Ubc13UEV1A

Ubc13Uev1A refers to the heterodimeric ubiquitin-conjugating enzyme complex formed by Ubc13 (UBE2N) and Uev1A (UBE2V1) in humans and many other eukaryotes. This complex is a noncanonical E2 pair that specifically catalyzes the formation of polyubiquitin chains linked through lysine 63 (K63).

The Ubc13Uev1A complex consists of a catalytic subunit, Ubc13, and a noncatalytic cofactor, Uev1A. Ubc13 possesses a catalytic cysteine that forms a thioester bond with ubiquitin, enabling chain elongation, while Uev1A lacks an active site cysteine and does not form Ub thioesters. Instead, Uev1A binds ubiquitin and orients it to promote the construction of K63-linked chains. The heterodimer works in concert with specific E3 ligases to transfer ubiquitin to substrates and to choose the Lys63 linkage over other linkage types.

Functionally, the Ubc13Uev1A complex is central to signaling pathways rather than proteasomal degradation. It drives the assembly of K63-linked polyubiquitin chains involved in DNA damage tolerance and repair (notably PCNA ubiquitination during translesion synthesis) and in innate and inflammatory signaling, including NF-κB activation through substrates recruited by E3 ligases such as TRAF6. The complex also participates in chromatin-based responses to DNA double-strand breaks through similar ubiquitin signaling networks.

Alterations in Ubc13 or Uev1A expression or activity can impact genome stability and immune signaling, and dysregulation has been associated with inflammatory diseases and some cancers. Because of its specific role in nondegradative ubiquitination, the Ubc13Uev1A axis is explored as a potential target for therapies aimed at modulating immune and DNA damage responses.