DNA polymerase κ (pol κ) is a member of the Y-family DNA polymerases that perform translesion synthesis. Single nucleotide polymorphisms in pol κ have been implicated in several different cancers. The primer extension activity and single-nucleotide incorporation kinetics of nine variants of pol κ were investigated experimentally with DNA containing correct base pairs at the primer terminus and mismatches. These variants were grouped into having either more, similar, or less activity to the wild-type (WT) protein. The WT and five variants, spanning across those three categories, were then simulated using molecular dynamics (MD) with either the correctly- or incorrectly-matched incoming nucleotide triphosphate. Several notable changes are seen between the systems, and structural differences show a similar pattern to those found experimentally. Most notably, mutants that were identified as less active with the correct incoming nucleotide shared structural characteristics with the WT structure with the incorrect incoming nucleotide. These results suggest that there may be different conformations for pol κ activity that are codependent on protein variant and DNA adduct identity.

Computational investigation of single nucleotide polymorphisms in human DNA polymerase κ

2019 Spring National Meeting

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