Title: Loss of PPP2R2A inhibits homologous recombination DNA repair and predicts tumor sensitivity to PARP inhibition
Authors: Kalev, Peter ×
Simicek, Michal
Vazquez, Iria
Munck, Sebastian
Chen, Liping
Soin, Thomas
Danda, Natasha
Chen, Wen
Sablina, Anna #
Issue Date: Dec-2012
Publisher: Waverly Press
Series Title: Cancer Research vol:72 issue:24 pages:6414-6424
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 G1/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 poly(ADP-ribose) polymerase (PARP). We found that 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.
ISSN: 0008-5472
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory for Mechanisms of Cell Transformation (VIB-KU Leuven Centre for Cancer Biology)
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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