title: Loss of PPP2R2A inhibits homologous recombination DNA repair and predicts tumor sensitivity to PARP inhibition.
abstract: Reversible phosphorylation plays a critical role in DNA repair. Here, we report the results of a loss-of-function screen that identifies the PP2A heterotrimeric serine/threonine phosphatases PPP2R2A, PPP2R2D, PPP2R5A, and PPP2R3C in double-strand break (DSB) repair. In particular, we found that PPP2R2A-containing complexes directly dephosphorylated ATM at S367, S1893, and S1981 to regulate its retention at DSB sites. Increased ATM phosphorylation triggered by PPP2R2A attenuation dramatically upregulated the activity of the downstream effector kinase CHK2, resulting in G(1) to S-phase cell-cycle arrest and downregulation of BRCA1 and RAD51. In tumor cells, blocking PPP2R2A thereby impaired the high-fidelity homologous recombination repair pathway and sensitized cells to small-molecule inhibitors of PARP. We found that PPP2R2A was commonly downregulated in non-small cell lung carcinomas, suggesting that PPP2R2A status may serve as a marker to predict therapeutic efficacy to PARP inhibition. In summary, our results deepen understanding of the role of PP2A family phosphatases in DNA repair and suggest PPP2R2A as a marker for PARP inhibitor responses in clinic.
authors.affiliation: VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Kalev
authors.forename: Michal
authors.initials: M
authors.lastname: Simicek
authors.forename: Iria
authors.initials: I
authors.lastname: Vazquez
authors.forename: Sebastian
authors.initials: S
authors.lastname: Munck
authors.forename: Liping
authors.initials: L
authors.lastname: Chen
authors.forename: Thomas
authors.initials: T
authors.lastname: Soin
authors.forename: Natasha
authors.initials: N
authors.lastname: Danda
authors.forename: Wen
authors.initials: W
authors.lastname: Chen
authors.forename: Anna
authors.initials: A
authors.lastname: Sablina
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000502:physiology; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017353:Gene Deletion; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051379:Mice; D009369:Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011379:Prognosis; D054648:Protein Phosphatase 2 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D059767:Recombinational DNA Repair / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; C512974:PPP2R2A protein, human; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D054648:Protein Phosphatase 2