Systems biology approach identifies the kinase Csnk1a1 as a regulator of the DNA damage response in embryonic stem cells

TY - JOUR

T1 - Systems biology approach identifies the kinase Csnk1a1 as a regulator of the DNA damage response in embryonic stem cells

AU - Carreras Puigvert, Jordi

AU - von Stechow, Louise

AU - Siddappa, Ramakrishnaiah

AU - Pines, Alex

AU - Bahjat, Mahnoush

AU - Haazen, Lizette C J M

AU - Olsen, Jesper Velgaard

AU - Vrieling, Harry

AU - Meerman, John H N

AU - Mullenders, Leon H F

AU - van de Water, Bob

AU - Danen, Erik H J

PY - 2013/1/22

Y1 - 2013/1/22

N2 - 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.

AB - 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.

KW - Animals

KW - Apoptosis

KW - Casein Kinase I

KW - Cell Line

KW - DNA Damage

KW - Embryonic Stem Cells

KW - Mice

KW - Pluripotent Stem Cells

KW - RNA Interference

KW - Systems Biology

KW - Transcriptome

KW - Tumor Suppressor Protein p53

KW - Wnt Signaling Pathway

UR - http://www.scopus.com/inward/record.url?scp=84872733084&partnerID=8YFLogxK

U2 - 10.1126/scisignal.2003208

DO - 10.1126/scisignal.2003208

M3 - Journal article

C2 - 23354688

AN - SCOPUS:84872733084

SN - 1945-0877

VL - 6

SP - ra5

JO - Science Signaling

JF - Science Signaling

IS - 259

ER -