Abstract 2228 The RNAi pathway contributes to genome stability during the p53 response to oncogene stress

Genomic instability during cellular senescence promotes escape from this critical tumor suppressor mechanism in premalignant lesions. p53 is implicated in a majority of cancers and is a crucial tumor suppressor that can trigger senescence in cells undergoing oncogenic stress. The discovery of mechanisms maintaining genome stability during this process will advance our understanding of senescence escape and tumorigenesis. Our goal is to determine the roles of regulatory RNAs during the p53 response and the maintenance of genome stability in senescent cells. Using mouse cells for inducible p53 reconstitution in tumor cells or inducible RNA interference (RNAi) in stem cells, we previously defined long noncoding RNAs acting in the p53 response and small noncoding RNAs of the RNAi pathway that function in the maintenance of genome stability, respectively. Here we address how RNAi contributes to genome stability during oncogene-induced senescence (OIS). We generated lung adenocarcinoma cell lines with dual conditional p53 and RNAi function, KRAS G12D / +;p53 LSL / LSL; Rosa26-CreERT2; Tet-Dicer HA / -, called KPRD. The dual temporal control of these pathways permits enhanced resolution of the gene network and cellular responses activated during OIS. We found KPRD cells depleted of Dicer have a distinct cell cycle progression phenotype in the absence of p53 and during the induction of senescence. Dicer-depleted KPRD cells also display increased genomic instability during the transformation into a senescent state. We will present the characterization of this cell system and connect the cellular responses to known Dicer-mediated mechanisms contributing to the genome stability in OIS. This project was made possible by funding from the NIH (1R01GM143536-01) and the Kure It Cancer Research Award.