The Rev1‐Pol ζ Mutasome

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Rev1 and DNA polymerase ζ (Pol ζ) play key roles in DNA translesion synthesis (TLS) and are largely responsible for both spontaneous and damage‐induced mutagenesis in eukaryotic cells. Pol ζ is a 4‐subunit complex (Rev7‐Rev3‐Pol31‐Pol32). The Pol31 and Pol32 subunits of Pol δ bind the Rev3 catalytic subunit of Pol ζ, and those subunits are required for PCNA‐dependent TLS by Pol ζ.The catalytic activity of Rev1 is largely dispensable for mutagenesis, however the interactions of Rev1 with mono‐ubiquitinated PCNA and with Pol ζ are essential. This suggests that Rev1 may act as a scaffold for TLS. We have identified a conserved regulatory motif (M1) in Rev1 that, when mutated results in a large stimulation of Pol ζ replication activity. Stimulation requires the interaction domains between Rev1 and Pol ζ, and is absolutely dependent on the presence of PCNA. However, the catalytic activity of Rev1 is not required. We hypothesize that the M1 motif participates in a negative regulation of Pol ζ‐mediated TLS that is relieved upon Rev1 modification during DNA damage response, which then leads to the initiation of mutagenesis.