Inhibition of DNA damage-induced apoptosis through Cdc7-mediated stabilization of Tob.
BACKGROUND
Preventing unnecessary cell death is essential for DNA-damaged cells to carry out the DNA repair process.


RESULTS
Cdc7 inhibits the Cul4-DDB1(Cdt2)-dependent Tob degradation.


CONCLUSIONS
Cdc7 enables mild DNA-damaged cells to keep their viability by competing with the Tob degradation system.


CONCLUSIONS
Cells deal with moderate DNA damage not only by cessation of the cell cycle but also through direct mediated pro-survival signaling. Cells respond to DNA damage by activating alternate signaling pathways that induce proliferation arrest or apoptosis. The correct balance between these two pathways is important for maintaining genomic integrity and preventing unnecessary cell death. The mechanism by which DNA-damaged cells escape from apoptosis during DNA repair is poorly understood. We show that the DNA replication-initiating kinase Cdc7 actively prevents unnecessary death in DNA-damaged cells. In response to mild DNA damage, Tob levels increase through both a transcriptional mechanism and protein stabilization, resulting in inhibition of pro-apoptotic signaling. Cells lacking Cdc7 expression undergo apoptosis after mild DNA damage, where Cul4-DDB1(Cdt2) induces Tob ubiquitination and subsequent degradation. Cdc7 phosphorylates and interacts with Tob to inhibit the Cul4-DDB1(Cdt2)-dependent Tob degradation. Thus, Cdc7 defines an essential pro-survival signaling pathway by contributing to stabilization of Tob, thereby the viability of DNA-damaged cells being maintained.
Department of Cancer Biology, Division of Oncology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Tokyo 108-8639, Japan.
Toru
T
Suzuki
Junko
J
Tsuzuku
Akiyo
A
Hayashi
Yasushi
Y
Shiomi
Hiroko
H
Iwanari
Yasuhiro
Y
Mochizuki
Takao
T
Hamakubo
Tatsuhiko
T
Kodama
Hideo
H
Nishitani
Hisao
H
Masai
Tadashi
T
Yamamoto
D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; C429530:DTL protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C098669:TOB1 protein, human; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; C068619:CDC7 protein, human; D017346:Protein Serine-Threonine Kinases