Translesion DNA synthesis provides a mechanism in which organisms can tolerate DNA damage by replicating through the damage in an error free or error prone manner. DNA Polymerase kappa (Pol κ) is a member of translesion DNA polymerases and has been shown to be involved during the extension steps of lesion bypass. The three-dimensional structure of Pol κ reveals a unique structural feature within the N-terminal region of the protein known as the N-clasp that is essential for its function. Upon binding to DNA template, the N-clasp domain completely encloses the DNA by bridging the PAD and thumb domains. To provide a better understanding of the role of the N-clasp domain, a variety of single amino acid substitutions were generated within the N-clasp that are also found as somatic mutations in cancer. The single-nucleotide polymorphism S47F has decreased affinity for choosing the correct nucleotide and an increased likelihood of causing frameshift mutations. The mutation S47A also displayed decreased effectiveness in translesion synthesis. Taken together, these results suggest that S47 is important to the functionality of Pol κ. Current investigations have been focused on the effects of these SNP mutations with a high-throughput fluorescence-based displacement assay.

Investigation into the efficiency of human Pol κ containing SNPs in the N-Clasp

251st National Meeting (2016)

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