Loss of PPP2R2A inhibits homologous recombination DNA repair and predicts tumor sensitivity to PARP inhibition

Kalev, Peter; Simicek, Michal; Vázquez Urio, Iria; Munck, Sebastian; Chen, Liping; Soin, Thomas; Danda, Natasha; Chen, Wen; Sablina, Anna

Loss of PPP2R2A inhibits homologous recombination DNA repair and predicts tumor sensitivity to PARP inhibition

dc.contributor.author	Kalev, Peter
dc.contributor.author	Simicek, Michal
dc.contributor.author	Vázquez Urio, Iria
dc.contributor.author	Munck, Sebastian
dc.contributor.author	Chen, Liping
dc.contributor.author	Soin, Thomas
dc.contributor.author	Danda, Natasha
dc.contributor.author	Chen, Wen
dc.contributor.author	Sablina, Anna
dc.contributor.department	Ciencias	es_ES
dc.contributor.department	Zientziak	eu
dc.date.accessioned	2025-01-14T09:41:19Z
dc.date.available	2025-01-14T09:41:19Z
dc.date.issued	2012-10-18
dc.date.updated	2025-01-14T09:37:07Z
dc.description.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 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.	en
dc.description.sponsorship	This work was supported by FWO (ZKC2592-00_WO1) and a Distinguished Young Scholar of National Nature Science Foundation of China (NSFC 30925029). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
dc.format.mimetype	application/pdf	en
dc.format.mimetype	application/zip	en
dc.identifier.citation	Kalev, P., Simicek, M., Vazquez, I., Munck, S., Chen, L., Soin, T., Danda, N., Chen, W., Sablina, A. (2012). Loss of PPP2R2A inhibits homologous recombination DNA repair and predicts tumor sensitivity to PARP inhibition. Cancer Research, 72(24), 6414-6424. https://doi.org/10.1158/0008-5472.CAN-12-1667.
dc.identifier.doi	10.1158/0008-5472.CAN-12-1667
dc.identifier.issn	0008-5472
dc.identifier.uri	https://academica-e.unavarra.es/handle/2454/52912
dc.language.iso	eng
dc.publisher	American Association for Cancer Research
dc.relation.ispartof	Cancer Research (2012), vol. 72, núm. 24
dc.relation.publisherversion	https://doi.org/10.1158/0008-5472.CAN-12-1667
dc.rights	© 2012 American Association for Cancer Research. This Accepted Manuscript is licensed under a Creative Commons Attribution 4.0 International License.
dc.rights.accessRights	info:eu-repo/semantics/openAccess
dc.rights.uri	https://creativecommons.org/licenses/by/4.0/
dc.subject	PP2A	en
dc.subject	ATM	en
dc.subject	DNA repair	en
dc.subject	Cancer	en
dc.subject	PARP inhibition	en
dc.title	Loss of PPP2R2A inhibits homologous recombination DNA repair and predicts tumor sensitivity to PARP inhibition	en
dc.type	info:eu-repo/semantics/article
dc.type.version	info:eu-repo/semantics/acceptedVersion
dspace.entity.type	Publication
relation.isAuthorOfPublication	3762d67a-d18f-4f29-8eee-8b4c20793cd8
relation.isAuthorOfPublication.latestForDiscovery	3762d67a-d18f-4f29-8eee-8b4c20793cd8