Rad18

Rad18 is a conserved RING finger E3 ubiquitin ligase that participates in DNA damage tolerance in eukaryotic cells. In yeast and mammals, Rad18 forms a functional complex with the E2 enzyme Rad6 to regulate the ubiquitination of PCNA, the sliding clamp that encircles DNA during replication.

At replication forks encountering DNA lesions, Rad18–Rad6 monoubiquitinates PCNA at lysine 164. This post-translational modification serves as a recruitment signal for translesion synthesis (TLS) polymerases such as Pol η, Pol ι, and Pol κ, enabling replication to continue past lesions. The outcome can be mutagenic or less so depending on the polymerase engaged.

In higher eukaryotes, PCNA monoubiquitination by Rad18 can be extended to K63-linked polyubiquitin chains by other factors (for example SHPRH or HLTF), promoting an error-free template switching pathway for lesion bypass, though monoubiquitination remains a critical initiating event.

Rad18 localizes to replication forks and DNA damage foci in response to replication stress and interacts with PCNA and other replication proteins. Genetic or functional loss of Rad18 leads to increased sensitivity to DNA-damaging agents, reduced efficiency of TLS, and higher mutation rates, underscoring its role in maintaining genome stability. The Rad18–Rad6 pathway is evolutionarily conserved from yeast to humans and is a central component of the cellular response to replication-blocking lesions.