Abstract 1764: Overexpression of the DNA repair regulator PARI in pancreatic cancers promotes genomic instability and tumorigenesis.

Abstract Inappropriate homologous recombination (HR) causes genomic instability and cancer. We recently showed that the protein PARI, containing a UvrD-like helicase domain, is a novel PCNA interacting partner, required for preservation of genome stability in human and DT40 chicken cells (Moldovan et al, Molecular Cell 2012). Using cell-based and biochemical assays, we showed that PARI restricts unscheduled recombination by interfering with the formation of RAD51-DNA HR structures. Thus, we proposed that PARI is a long sought-after factor that suppresses inappropriate recombination events at mammalian replication forks. We recently found that PARI is specifically overexpressed in pancreatic cancer cells (O'Connor et al, Cancer Research, in revision). PARI up-regulation results in DNA repair deficiency and genomic instability. Importantly, PARI knockdown compromises the proliferation of pancreatic cancer cells in vitro. PARI depletion results in an altered cell cycle, defined by S-phase accumulation, perturbed DNA replication, and activation of the DNA damage response pathway in the absence of exogenous DNA damage. Moreover, we found that in pancreatic cancer cells, PARI overexpression results in DNA damage tolerance by promoting replication of damaged DNA. Finally, using a xenograft tumor model in nude mice we show that PARI knockdown reduces pancreatic tumor growth in vivo. Thus, our work suggests that PARI is a potential target for pancreatic ductal adenocarcinoma therapy. Citation Format: Kevin O'Connor, Donniphat Dejsuphong, Alan D'Andrea, George-Lucian Moldovan. Overexpression of the DNA repair regulator PARI in pancreatic cancers promotes genomic instability and tumorigenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1764. doi:10.1158/1538-7445.AM2013-1764