title: DNA-PKCS binding to p53 on the p21WAF1/CIP1 promoter blocks transcription resulting in cell death.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Hill
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Madureira
authors.forename: David M
authors.initials: DM
authors.lastname: Waisman
authors.forename: Patrick W K
authors.initials: PW
authors.lastname: Lee
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics; D051747:DNA-Activated Protein Kinase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational / Q000235:genetics; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009687:Nuclear Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human