Expression profiling of cellular transformation induced by tumor‐associated DNA polymerase beta variant I260M

Abstract

DNA damage in vivo is estimated to occur upwards of 20,000 lesions per cell daily. Base excision repair (BER) resolves abasic sites and damaged bases. During BER, DNA polymerase β (Pol β) fills DNA gaps after excision of damaged bases. Approximately 30% of human tumors express Pol β variants not present in normal tissue. Many have altered fidelity and activity in vitro and induce cellular transformation. Prostate tumor variant I260M transforms cells and is a sequence‐context dependent mutator. To test the hypothesis that mutations induced in vivo by I260M lead to transformation, we characterized the genome‐wide expression profile of a clone expressing I260M compared to its non‐induced counterpart. Using a 1.5 fold cutoff with a false discovery rate of <0.05, 912 genes were found to be altered. Gene Ontology clusters were analyzed using Ingenuity Pathways Analysis to identify altered gene networks and associated nodes. Three nodes of interest with unaltered expression exhibited dysregulation of downstream targets. One node, peroxisome proliferator activator protein γ (PPARG), was found to have a coding mutation present only in transformed cells. PPARG is a transcription factor implicated as a tumor suppressor. This mutation may have contributed to driving cellular transformation. We conclude that I260M induces cellular transformation by a mutational mechanism.This work was supported by 5R01CA080830 to J.S.