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Sci. Signal., 22 January 2013
Vol. 6, Issue 259, p. ra5
[DOI: 10.1126/scisignal.2003208]

RESEARCH ARTICLES

Systems Biology Approach Identifies the Kinase Csnk1a1 as a Regulator of the DNA Damage Response in Embryonic Stem Cells

Jordi Carreras Puigvert1*, Louise von Stechow1,2*, Ramakrishnaiah Siddappa1,2, Alex Pines2,3, Mahnoush Bahjat1, Lizette C. J. M. Haazen1, Jesper V. Olsen4, Harry Vrieling3, John H. N. Meerman1, Leon H. F. Mullenders3, Bob van de Water1, and Erik H. J. Danen1{dagger}

1 Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, P. O. Box 9502, 2300 RA Leiden, the Netherlands.
2 Netherlands Toxicogenomics Center, 2300 RA Leiden, the Netherlands.
3 Department of Toxicogenetics, Leiden University Medical Center, P. O. Box 9600, 2300 RC Leiden, the Netherlands.
4 Department of Proteomics, Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3b, 2200 Copenhagen N, Denmark.

* These authors contributed equally to this work.

Abstract: In pluripotent stem cells, DNA damage triggers loss of pluripotency and apoptosis as a safeguard to exclude damaged DNA from the lineage. An intricate DNA damage response (DDR) signaling network ensures that the response is proportional to the severity of the damage. We combined an RNA interference screen targeting all kinases, phosphatases, and transcription factors with global transcriptomics and phosphoproteomics to map the DDR in mouse embryonic stem cells treated with the DNA cross-linker cisplatin. Networks derived from canonical pathways shared in all three data sets were implicated in DNA damage repair, cell cycle and survival, and differentiation. Experimental probing of these networks identified a mode of DNA damage–induced Wnt signaling that limited apoptosis. Silencing or deleting the p53 gene demonstrated that genotoxic stress elicited Wnt signaling in a p53-independent manner. Instead, this response occurred through reduced abundance of Csnk1a1 (CK1α), a kinase that inhibits β-catenin. Together, our findings reveal a balance between p53-mediated elimination of stem cells (through loss of pluripotency and apoptosis) and Wnt signaling that attenuates this response to tune the outcome of the DDR.

{dagger} To whom correspondence should be addressed. E-mail: e.danen{at}lacdr.leidenuniv.nl

Citation: J. Carreras Puigvert, L. von Stechow, R. Siddappa, A. Pines, M. Bahjat, L. C. J. M. Haazen, J. V. Olsen, H. Vrieling, J. H. N. Meerman, L. H. F. Mullenders, B. van de Water, E. H. J. Danen, Systems Biology Approach Identifies the Kinase Csnk1a1 as a Regulator of the DNA Damage Response in Embryonic Stem Cells. Sci. Signal. 6, ra5 (2013).

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