Cryo-EM structure of translesion DNA synthesis polymerase zeta with a base pair mismatch

The structure of mismatched DNA-Pol zeta ternary complex provides a basis for understanding what makes Pol zeta adept at extending DNA synthesis past mismatched base pairs. The B-family multi-subunit DNA polymerase zeta (Pol zeta) is important for translesion DNA synthesis (TLS) during replication, due to its ability to extend synthesis past nucleotides opposite DNA lesions and mismatched base pairs. We present a cryo-EM structure of Saccharomyces cerevisiae Pol zeta with an A:C mismatch at the primer terminus. The structure shows how the Pol zeta active site responds to the mismatched duplex DNA distortion, including the loosening of key protein-DNA interactions and a fingers domain in an "open" conformation, while the incoming dCTP is still able to bind for the extension reaction. The structure of the mismatched DNA-Pol zeta ternary complex reveals insights into mechanisms that either stall or favor continued DNA synthesis in eukaryotes.