Abstract
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 ζ catalytic subunit interacts with accessory subunits of replicative DNA Pol δ. 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 δ and Pol ζ contain a [4Fe-4S] cluster coordinated by four cysteines. Amino acid changes in Pol ζ that prevent the assembly of the [4Fe-4S] cluster abrogate Pol ζ 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 δ and Pol ζ catalytic subunits on a preassembled complex of accessory proteins retained on DNA during translesion DNA synthesis.
Highlights
DNA polymerase (Pol) ␦ is involved in UV light-induced mutagenesis by an unknown mechanism
The C-terminal domain (CTD) of Pol ␣ and Pol ⑀ are significantly larger in size and share similar topology with -strand-based zinc fingers
Mutations disrupting the interaction of the B-subunit with the catalytic subunit were mapped mainly to this disordered surface, indicating that it is a docking site for the Pol ␦ CTD [34]
Summary
DNA polymerase (Pol) ␦ is involved in UV light-induced mutagenesis by an unknown mechanism. Disruption of the gene encoding the catalytic subunit (REV3) results in a severe decrease in spontaneous and damage-induced mutagenesis, embryonic lethality in mice, and chromosomal instability [8] These properties put Pol in a central position in the cellular machinery regulating the outcomes of DNA damage, a process that triggers many diseases, including cancer. Combined with electron microscopy studies of Pol ␣ and Pol ⑀ and small angle x-ray scattering studies of Pol ␦, these data indicate that the CTD is organized as a separate domain connected to the catalytic core by a flexible linker [13,14,15] This indicates that CTD is a universal tether between the catalytic core and accessory subunits in replicative DNA polymerases. We present an explanation for this by demonstrating that Pol and the catalytic subunit of Pol ␦ share the accessory B- and C-subunits of Pol ␦
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