Genetic Screening for Synthetic Lethal Partners of Polynucleotide Kinase/Phosphatase: Potential for Targeting SHP-1-Depleted Cancers

Oncology, University of Alberta.
Cancer Research (Impact Factor: 9.33). 09/2012; 72(22). DOI: 10.1158/0008-5472.CAN-12-0939
Source: PubMed


A genetic screen using a library of 6961 siRNAs led to the identification of SHP1 (PTPN6), a tumor suppressor frequently mutated in malignant lymphomas, leukemias and prostate cancer, as a potential synthetic lethal partner of the DNA repair protein polynucleotide kinase/phosphatase (PNKP). After confirming the partnership with SHP-1, we observed that co-depletion of PNKP and SHP-1 induced apoptosis. A T-cell lymphoma cell line that is SHP-1-deficient (Karpas 299) was shown to be sensitive to a chemical inhibitor of PNKP, but resistance was restored by expression of wild-type SHP-1 in these cells. We determined that while SHP-1 depletion does not significantly impact DNA strand-break repair, it does amplify the level of reactive oxygen species (ROS) and elevate endogenous DNA damage. The ROS scavenger WR1065 afforded protection to SHP-1 depleted cells treated with the PNKP inhibitor. We propose that co-disruption of SHP-1 and PNKP leads to an increase in DNA damage that escapes repair, resulting in the accumulation of cytotoxic double-strand breaks and induction of apoptosis. This supports an alternative paradigm for synthetic lethal partnerships that could be exploited therapeutically.

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Available from: Michael Weinfeld, Jan 06, 2015
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