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

Arvindhan Nagarajan; Shaillay Kumar Dogra; Alex Y Liu; Michael R Green; Narendra Wajapeyee

doi:10.1128/MCB.01542-13

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

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

Authors

Arvindhan Nagarajan¹, Shaillay Kumar Dogra², Alex Y Liu¹, Michael R Green³, Narendra Wajapeyee⁴

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Apoptosis Regulatory Proteins
Ataxia Telangiectasia Mutated Proteins / metabolism
COP9 Signalosome Complex
Cell Cycle Checkpoints*
Cell Line
Cell Transformation, Neoplastic / metabolism*
Cell Transformation, Neoplastic / pathology
Cyclin-Dependent Kinase 6 / metabolism
DNA Damage*
DNA Methylation
Epigenesis, Genetic
G2 Phase Cell Cycle Checkpoints
Gene Silencing
Humans
Intracellular Signaling Peptides and Proteins / chemistry
Intracellular Signaling Peptides and Proteins / metabolism*
Mice
Molecular Sequence Data
Oncogenes*
Peptide Hydrolases / metabolism
Phosphoproteins / chemistry
Phosphoproteins / metabolism*
Proteasome Endopeptidase Complex / metabolism
Protein Binding
Protein Processing, Post-Translational
Protein Stability
Proteolysis
Two-Hybrid System Techniques
Ubiquitination
cdc25 Phosphatases / metabolism
ras Proteins / metabolism

Substances

Apoptosis Regulatory Proteins
Intracellular Signaling Peptides and Proteins
PEA15 protein, human
Phosphoproteins
Ataxia Telangiectasia Mutated Proteins
Cyclin-Dependent Kinase 6
cdc25 Phosphatases
Peptide Hydrolases
COPS5 protein, human
COP9 Signalosome Complex
Proteasome Endopeptidase Complex
ras Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding