Y-family DNA polymerases and their role in tolerance of cellular DNA damage

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Abstract
Replication past DNA damage by translesion synthesis (TLS) requires specialized DNA polymerases, most of which belong to the Y-family. They have open structures that can accommodate damaged bases in their active sites and are conserved in all organisms. Y-family members have specialized features enabling them to synthesize DNA past specific lesions. As an example, the main ultraviolet light photoproduct is constrained by DNA polymerase η (Pol η) in a molecular splint, such that base pairing is maintained despite the distortion caused by the lesion. As these polymerases have a low fidelity on undamaged DNA, they are regulated at several different levels. In Escherichia coli, their concentration is under the control of the SOS response — low in undamaged cells but induced by damage. In vertebrate cells, they are concentrated in replication factories in S phase, especially following DNA damage, but are also specifically regulated at stalled forks within these factories. The sliding clamp accessory protein PCNA (proliferating cell nuclear antigen) is a key regulator, and all family members have PCNA-binding motifs. When the replication fork is stalled at damage, PCNA is ubiquitylated. This increases the affinity of the polymerases for PCNA by virtue of the ubiquitin-binding motifs present in all of the Y-family polymerases. Under most circumstances, REV1 has a non-catalytic role and acts as a scaffold by virtue of a carboxy-terminal sequence that binds the other Y-family polymerases. Ubiquitylation of PCNA is required for carrying out TLS across gaps behind the replication forks, whereas REV1 is involved in directing TLS at the stalled forks.