Human DNA polymerase κ synthesizes DNA with extraordinarily low fidelity

Escherichia coli DNA polymerase IV encoded by the dinB gene is involved in untargeted mutagenesis, Its human homologue is DNA polymerase kappa (Pol kappa) encoded by the DINB1 gene. Our recent studies have indicated that human Pol kappa is capable of both error-free and error-prone translesion DNA synthesis in vitro. However, it is not known whether human Pol kappa also plays a role in untargeted mutagenesis, To examine this possibility, we have measured the fidelity of human Pol kappa during DNA synthesis from undamaged templates. Using kinetic measurements of nucleotide incorporations and a fidelity assay with gapped M13mp2 DNA, we show that human Pol kappa synthesizes DNA with extraordinarily low fidelity. At the lacZ alpha target gene, human Pol kappa made on average one error for every 200 nucleotides synthesized, with a predominant T-->G transversion mutation at a rate of 1/147. The overall error rate of human Pol kappa is 1.7-fold lower than human Pol eta, but 33-fold higher than human Pol beta, a DNA polymerase with very low fidelity. Thus, human Pol kappa is one of the most inaccurate DNA polymerases known. These results support a role for human Pol kappa in untargeted mutagenesis surrounding a DNA lesion and in DNA regions without damage.