title: 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.affiliation: Experimental Oncology, Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Todd R
authors.initials: TR
authors.lastname: Mereniuk
authors.forename: Robert A
authors.initials: RA
authors.lastname: Maranchuk
authors.forename: Anja
authors.initials: A
authors.lastname: Schindler
authors.forename: Jonathan
authors.initials: J
authors.lastname: Penner-Chea
authors.forename: Gary K
authors.initials: GK
authors.lastname: Freschauf
authors.forename: Samar
authors.initials: S
authors.lastname: Hegazy
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
authors.forename: Edan
authors.initials: E
authors.lastname: Foley
authors.forename: Michael
authors.initials: M
authors.lastname: Weinfeld
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005820:Genetic Testing; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D061986:MCF-7 Cells; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000172:deficiency* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection
chemical_list: D034741:RNA, Small Interfering; C530380:PNKP protein, human; D017853:Phosphotransferases (Alcohol Group Acceptor); D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D045643:DNA Repair Enzymes