Mms2Ubc13Rad5

Mms2-Ubc13-Rad5 is a eukaryotic protein complex that promotes error-free DNA damage tolerance by polyubiquitinating PCNA (proliferating cell nuclear antigen) at lysine 164 with K63-linked chains. The complex is composed of Mms2, a noncatalytic ubiquitin-conjugating enzyme variant; Ubc13, a specialized E2 ubiquitin-conjugating enzyme; and Rad5, a DNA damage tolerance factor containing a RING finger E3 ligase domain and a helicase-like region. In yeast, this trio acts downstream of the Rad6-Rad18–mediated monoubiquitination of PCNA to switch the pathway from translesion synthesis to an error-free template-switching mechanism.

Mechanism: Following replication stress, PCNA is first monoubiquitinated to initiate lesion bypass. If the cell favors an error-free response, the Mms2-Ubc13 complex forms a functional E2 module that, with Rad5 as an E3 ligase, catalyzes the extension of the ubiquitin signal from a single unit to a K63-linked polyubiquitin chain on PCNA. This modification promotes template switching, allowing the replication machinery to use the undamaged sister chromatid as a template to bypass the lesion without introducing mutations.

Biological significance: The Mms2-Ubc13-Rad5 pathway contributes to genome stability by enabling replication to proceed past DNA lesions with reduced mutagenesis. It operates in parallel with other postreplication repair routes and interacts with a network of factors involved in DNA damage tolerance. Disruption of any component can increase sensitivity to DNA-damaging agents and elevate genomic instability.

Evolutionary context: While the yeast complex exemplifies the canonical Mms2-Ubc13-Rad5 arrangement, the broader eukaryotic PCNA polyubiquitination system is conserved, with higher organisms employing related Ubc13-MMS2-like modules and alternative E3 ligases (such as HLTF and SHPRH) to achieve template switching.