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Inhibition of DNA damage-induced apoptosis through Cdc7-mediated stabilization of Tob.


ABSTRACT:

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.

Conclusion

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

Significance

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.

SUBMITTER: Suzuki T 

PROVIDER: S-EPMC3504742 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Publications

Inhibition of DNA damage-induced apoptosis through Cdc7-mediated stabilization of Tob.

Suzuki Toru T   Tsuzuku Junko J   Hayashi Akiyo A   Shiomi Yasushi Y   Iwanari Hiroko H   Mochizuki Yasuhiro Y   Hamakubo Takao T   Kodama Tatsuhiko T   Nishitani Hideo H   Masai Hisao H   Yamamoto Tadashi T  

The Journal of biological chemistry 20121012 48


<h4>Background</h4>Preventing unnecessary cell death is essential for DNA-damaged cells to carry out the DNA repair process.<h4>Results</h4>Cdc7 inhibits the Cul4-DDB1(Cdt2)-dependent Tob degradation.<h4>Conclusion</h4>Cdc7 enables mild DNA-damaged cells to keep their viability by competing with the Tob degradation system.<h4>Significance</h4>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 d  ...[more]

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