MMS2UBC13

MMS2-UBC13 is a conserved heterodimeric ubiquitin-conjugating enzyme complex that plays a key role in DNA damage tolerance. In Saccharomyces cerevisiae it consists of Mms2 (a noncatalytic ubiquitin-conjugating enzyme variant) paired with Ubc13 (an active E2 enzyme). In mammals the functional equivalent is the UBE2N–UBE2V1/UBE2V2 complex, where UBC13 corresponds to UBE2N and MMS2 corresponds to the noncatalytic UEV proteins.

The complex specializes in assembling Lysine-63-linked (Lys63) polyubiquitin chains, rather than the Lysine-48 chains associated with proteasomal degradation. Mms2 provides specificity for Lys63 chain formation, enabling Ubc13 to extend ubiquitin chains in a nondegradative signaling context. This activity is crucial for signaling events at sites of DNA damage and replication stress.

In the DNA damage response, MMS2-UBC13 coordinates with other factors to promote error-free damage bypass, most notably by polyubiquitinating PCNA (the sliding clamp) at stalled replication forks. In yeast, Mms2-Ubc13 works with Rad5 to drive template switching, an alternative replication pathway that bypasses lesions without introducing mutations. In higher eukaryotes, the complex participates in similar signaling networks and interacts with various E3 ligases and damage-response proteins to stabilize stalled forks and coordinate downstream repair processes.

The MMS2-UBC13 activity is essential for proper genome stability; defects lead to hypersensitivity to DNA damaging agents and impaired DNA damage tolerance. The complex is therefore a central component of the DNA damage response across eukaryotes, with conserved structural and functional features that underpin Lys63-linked ubiquitination signaling.