PARI overexpression promotes genomic instability and pancreatic tumorigenesis

Kevin W. O'Connor, Donniphat Dejsuphong, Eunmi Park, Claudia M. Nicolae, Alec C. Kimmelman, Alan D. D'Andrea, George Lucian Moldovan

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


Treatment options for patients with pancreatic ductal adenocarcinoma (PDAC) remain limited. Therapeutic targets of interest include mutated molecules that predispose to pancreatic cancer such as KRAS and TP53. Here, we show that an element of the homologous recombination pathway of DNA repair, the PARP-binding protein C12orf48/PARI (PARPBP), is overexpressed specifically in pancreatic cancer cells where it is an appealing candidate for targeted therapy. PARI upregulation in pancreatic cancer cells or avian DT40 cells conferred DNA repair deficiency and genomic instability. Significantly, PARI silencing compromised cancer cell proliferation in vitro, leading to cell-cycle alterations associated with S-phase delay, perturbed DNA replication, and activation of the DNA damage response pathway in the absence of DNA damage stimuli. Conversely, PARI overexpression produced tolerance to DNA damage by promoting replication of damaged DNA. In a mouse xenograft model of pancreatic cancer, PARI silencing was sufficient to reduce pancreatic tumor growth in vivo. Taken together, our findings offered a preclinical proof-of-concept for PARI as candidate therapeutic target to treat PDAC.

Original languageEnglish (US)
Pages (from-to)2529-2539
Number of pages11
JournalCancer Research
Issue number8
StatePublished - Apr 15 2013

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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