Translesion Synthesis Polymerases in the Prevention and Promotion of Carcinogenesis
Figure 1
Regulation of DNA lesion bypass in Saccharomyces cerevisiae and humans. Bulky DNA lesions can cause blockage of replicative polymerases and replication fork stalling. The ubiquitin conjugase/ubiquitin ligase pair Rad6/Rad18 is recruited to stalled replication forks where the proteins catalyze monoubiquitylation of PCNA at lysine 164. TLS proteins such as REV1 and have increased affinity for monoubiquitylated PCNA, which facilitates their recruitment and the completion of TLS. In yeast, Rad5 and the MMS2-Ubc13 complex (UBE2V2-UBE2N in humans) can catalyze polyubiquitylation of PCNA via lysine 63 of ubiquitin, which blocks TLS and activates error-free damage avoidance. Damage avoidance includes template switching, during which the nascent DNA strand from the sister duplex is used as an undamaged homologous template to replicate past the lesion. Humans express two Rad5 homologs, SHPRH and HLTF, and both catalyze K-63-linked polyubiquitylation of PCNA in human cells [12–15]. In yeast, Ubc9-Siz1 can attach the small ubiquitin-like modifier (SUMO) to lysine 164 of PCNA in a reaction that competes with Rad6/Rad18-mediated monoubiquitylation. PCNA SUMOylation at K-164 attracts the helicase Srs2 and prevents error-prone RAD52-dependent recombination. Reproduced with permission from Watson et al. [16].
