Genetic screening for synthetic lethal partners of polynucleotide kinase/phosphatase: potential for targeting SHP-1-depleted cancers.

Abstract

A genetic screen using a library of 6,961 siRNAs led to the identification of SHP-1 (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 codepletion 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 codisruption 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.

• Authors: Todd R Mereniuk, Robert A Maranchuk, Anja Schindler, Jonathan Penner-Chea, Gary K Freschauf, Samar Hegazy, Raymond Lai, Edan Foley, Michael Weinfeld
• Journal: Cancer research (Cancer Res) Vol. 72 Issue 22 Pg. 5934-44 (Nov 15 2012) ISSN: 1538-7445 [Electronic] United States
• PMID: 22962271 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• RNA, Small Interfering
• PNKP protein, human
• Phosphotransferases (Alcohol Group Acceptor)
• Protein Tyrosine Phosphatase, Non-Receptor Type 6
• DNA Repair Enzymes

Topics

• Adenocarcinoma (enzymology, genetics, pathology)
• Breast Neoplasms (enzymology, genetics, pathology)
• Cell Death (genetics)
• Cell Line, Tumor
• DNA Repair Enzymes (antagonists & inhibitors, genetics, metabolism)
• Female
• Genetic Testing
• Humans
• Lung Neoplasms (enzymology, genetics, pathology)
• MCF-7 Cells
• Phosphotransferases (Alcohol Group Acceptor) (antagonists & inhibitors, genetics, metabolism)
• Protein Tyrosine Phosphatase, Non-Receptor Type 6 (deficiency, metabolism)
• RNA, Small Interfering (genetics)
• Transfection