PEA15 Regulates the DNA Damage-Induced Cell Cycle Checkpoint and Oncogene-Directed Transformation

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.

ACKNOWLEDGMENTS

We thank Angelika Amon and Mark Hochstrasser for helpful discussions and David Stern for his useful comments on the manuscript. We thank Darryl Conte for editorial assistance.

N.W. is a translational scholar of the Sidney Kimmel Foundation for Cancer Research and is supported by a Young Investigator Award from the National Lung Cancer Partnership, Uniting against Lung Cancer, and the International Association for the Study of Lung Cancer, Melanoma Research Alliance and Melanoma Research Foundation. M.R.G. is an investigator of the Howard Hughes Medical Institute. This work was supported in part by a grant from the NIH (R01GM033977) to M.R.G.