p27Kip1 Is Required to Mediate a G1 Cell Cycle Arrest Downstream of ATM following Genotoxic Stress.
The DNA damage response (DDR) is a coordinated signaling network that ensures the maintenance of genome stability under DNA damaging stress. In response to DNA lesions, activation of the DDR leads to the establishment of cell cycle checkpoints that delay cell-cycle progression and allow repair of the defects. The tumor suppressor p27Kip1 is a cyclin-CDK inhibitor that plays an important role in regulating quiescence in a variety of tissues. Several studies have suggested that p27Kip1 also plays a role in the maintenance of genomic integrity. Here we demonstrate that p27Kip1 is essential for the establishment of a G1 checkpoint arrest after DNA damage. We also uncovered that ATM phosphorylates p27Kip1 on a previously uncharacterized residue (Ser-140), which leads to its stabilization after induction of DNA double-strand breaks. Inhibition of this stabilization by replacing endogenous p27Kip1 with a Ser-140 phospho-mutant (S140A) significantly sensitized cells to IR treatments. Our findings reveal a novel role for p27Kip1 in the DNA damage response pathway and suggest that part of its tumor suppressing functions relies in its ability to mediate a G1 arrest after the induction of DNA double strand breaks.
Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, Texas, United States of America.
Erica K
EK
Cassimere
Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, Texas, United States of America.
Claire
C
Mauvais
Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, Texas, United States of America.
Catherine
C
Denicourt
D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000528:radiation effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004249:DNA Damage; D016193:G1 Phase / Q000528:radiation effects; D059585:G1 Phase Cell Cycle Checkpoints / Q000528:radiation effects; D005720:Gamma Rays; D006801:Humans; D010766:Phosphorylation / Q000528:radiation effects; D010768:Phosphoserine / Q000378:metabolism; D055550:Protein Stability / Q000528:radiation effects; D016196:S Phase / Q000528:radiation effects; D015398:Signal Transduction / Q000528:radiation effects; D018874:Spheroids, Cellular / Q000473:pathology / Q000528:radiation effects; D013997:Time Factors
D050760:Cyclin-Dependent Kinase Inhibitor p27; D010768:Phosphoserine; D064007:Ataxia Telangiectasia Mutated Proteins