DNA Polymerase δ and ζ Switch by Sharing Accessory Subunits of DNA Polymerase δ

Translesion DNA synthesis is an important branch of the DNA damage tolerance pathway that assures genomic integrity of living organisms. The mechanisms of DNA polymerase (Pol) switches during lesion bypass are not known. Here, we show that the C-terminal domain of the Pol zeta catalytic subunit interacts with accessory subunits of replicative DNA Pol delta. We also show that, unlike other members of the human B-family of DNA polymerases, the highly conserved and similar C-terminal domains of Pol delta and Pol zeta contain a [4Fe-4S] cluster coordinated by four cysteines. Amino acid changes in Pol zeta that prevent the assembly of the [4Fe-4S] cluster abrogate Pol zeta function in UV mutagenesis. On the basis of these data, we propose that Pol switches at replication-blocking lesions occur by the exchange of the Pol delta and Pol zeta catalytic subunits on a preassembled complex of accessory proteins retained on DNA during translesion DNA synthesis.