DNA-PKCS binding to p53 on the p21WAF1/CIP1 promoter blocks transcription resulting in cell death
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1 Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
2 Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada
3 Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
Received: December 8, 2011; Accepted: December 9, 2011; Published: December 20, 2011;
Keywords: DNA-PKCs, p53, p21 transcription suppression
Patrick W.K. Lee, email:
A key determinant of p53-mediated cell fate following various DNA damage modalities is p21WAF1/CIP1 expression, with elevated p21 expression triggering cell cycle arrest and repressed p21 expression promoting apoptosis. We show that under pro-death DNA damage conditions, the DNA-dependent protein kinase (DNA-PKCS) is recruited to the p21 promoter where it forms a protein complex with p53. The DNA-PKCS-associated p53 displays post-translational modifications that are distinct from those under pro-arrest conditions, ablating p21 transcription and inducing cell death. Inhibition of DNA-PK activity prevents DNA-PKCS binding to p53 on the p21 promoter, restores p21 transcription and significantly reduces cell death. These data demonstrate that DNA-PKCS negatively regulates p21 expression by directly interacting with the p21 transcription machinery via p53, driving the cell towards apoptosis.
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