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 polymerase known. These results support a role for human Pol#kappa# in untargeted mutagenesis surrounding a DNA lesion and in DNA regions without damage.
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