Investigating the role of human DNA polymerases in mutational processes (360G-Wellcome-225678_Z_22_Z)

Cancer-causing mutational processes leave distinct footprints in the DNA, detectable using the computational approach of mutational signatures. While DNA replication and DNA polymerases are involved in practically all mutational processes, the mechanisms of how different polymerases contribute to individual mutational processes remain largely unknown. Here, I propose an interdisciplinary project to understand the role of polymerase errors in mutational processes, combining our new experimental technique for polymerase error measurement, computational method development, and analyses of sequencing data from ca. 40,000 cancer patients, several animal models, and cell lines. I aim to elucidate how the major replicative polymerases Polε and Polδ contribute to mutational signatures found in cancer patients deficient or proficient in post-replicative repair and to understand the role of translesion synthesis polymerases in mutational processes and treatment resistance. I will combine our results with publicly available data sets to build computational methods for polymerase signature detection in patient sequencing data and to create models for patient risk stratification and prediction of treatment response. This interdisciplinary approach will be used to bring mechanistic insight into the role of DNA polymerases in different mutational processes, predict personalised treatment plans, and lay foundations for development of novel treatments in the future.