Somatic Mutations in Catalytic Core ofPOLKReported in Prostate Cancer Alter Translesion DNA Synthesis


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Abstract

DNA polymerase kappa is a Y-family polymerase that participates to bypass the damaged DNA known as translesion synthesis (TLS) polymerase. Higher frequency of mutations in DNA polymerase kappa (POLK) recently been reported in prostate cancer. We sequenced entire exons of thePOLKgene on genomic DNA from 40 prostate cancers and matched normal samples. We identified that 28% of patients have somatic mutations in thePOLKgene of the prostate tumors. Mutations in these prostate cancers have somatic mutation spectra, which are dominated by C-to-T transitions. In the current study, we further investigate the effect of p.E29K, p.G154E, p.F155S, p.E430K, p.L442F, and p.E449K mutations on the biochemical properties of the polymerase in vitro, using TLS assay and nucleotide incorporation fidelity, following site-directed mutagenesis bacterial expression, and purification of the respective polymerase variants. We report that following missense mutations p.E29K, p.G154E, p.F155S, p.E430K, and p.L442F significantly diminished the catalytic efficiencies ofPOLKwith regard to the lesion bypass (AP site).POLKvariants show extraordinarily low fidelity by misincorporating T, C, and G as compared to wild-type variants. Taken together, these results suggest that interfering with normal polymerase kappa function by these mutations may be involved in prostate carcinogenesis.The catalytic core of human DNA polymerase Kappa is commonly mutated in prostate tumors. Missense human POLK mutations dramatically reduce (up to 100-fold) catalytic afficiency of lesion bypass.

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