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Mol Cell Biol. 2014 Jun;34(12):2264-82. doi: 10.1128/MCB.01542-13. Epub 2014 Apr 7.

PEA15 regulates the DNA damage-induced cell cycle checkpoint and oncogene-directed transformation.

Author information

1
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
2
Singapore Institute of Clinical Sciences, Agency for Science Technology and Research, Brenner Center for Molecular Medicine, Singapore, Singapore.
3
Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
4
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA narendra.wajapeyee@yale.edu.

Abstract

Regulation of the DNA damage response and cell cycle progression is critical for maintaining genome integrity. Here, we report that in response to DNA damage, COPS5 deubiquitinates and stabilizes PEA15 in an ATM kinase-dependent manner. PEA15 expression oscillates throughout the cell cycle, and the loss of PEA15 accelerates cell cycle progression by activating CDK6 expression via the c-JUN transcription factor. Cells lacking PEA15 exhibit a DNA damage-induced G2/M checkpoint defect due to increased CDC25C activity and, consequentially, higher cyclin-dependent kinase 1 (CDK1)/cyclin B activity, and accordingly they have an increased rate of spontaneous mutagenesis. We find that oncogenic RAS inhibits PEA15 expression and that ectopic PEA15 expression blocks RAS-mediated transformation, which can be partially rescued by ectopic expression of CDK6. Finally, we show that PEA15 expression is downregulated in colon, breast, and lung cancer samples. Collectively, our results demonstrate that tumor suppressor PEA15 is a regulator of genome integrity and is an integral component of the DNA damage response pathway that regulates cell cycle progression, the DNA-damage-induced G2/M checkpoint, and cellular transformation.

PMID:
24710276
PMCID:
PMC4054289
DOI:
10.1128/MCB.01542-13
[Indexed for MEDLINE]
Free PMC Article

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