p53 functions through stress- and promoter-specific recruitment of transcription initiation components before and after DNA damage.
The tumor suppressor protein p53 regulates transcriptional programs that control the response to cellular stress. We show that distinct mechanisms exist to activate p53 target genes as revealed by marked differences in affinities and damage-specific recruitment of transcription initiation components. p53 functions in a temporal manner to regulate promoter activity both before and after stress. Before DNA damage, basal levels of p53 are required to assemble a poised RNA polymerase II initiation complex on the p21 promoter. RNA pol II is converted into an elongating form shortly after stress but before p53 stabilization. Proapoptotic promoters, such as Fas/APO1, have low levels of bound RNA pol II but undergo damage-induced activation through efficient reinitiation. Surprisingly, in a p53-dependent process key basal factors TAFII250 and TFIIB assemble into the transcription machinery in a stress- and promoter-specific manner, behaving as differential cofactors for p53 action after distinct types of DNA damage.
Regulatory Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Joaquín M
JM
Espinosa
Ramiro E
RE
Verdun
Beverly M
BM
Emerson
D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004249:DNA Damage / Q000235:genetics*; D051548:Histone Acetyltransferases; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012319:RNA Polymerase II / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics*; D035381:TATA-Binding Protein Associated Factors / Q000378:metabolism; D035581:Transcription Factor TFIIB / Q000378:metabolism; D035362:Transcription Factor TFIID / Q000378:metabolism; D024363:Transcription Initiation Site / Q000502:physiology; D015533:Transcriptional Activation / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D019014:fas Receptor / Q000378:metabolism
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D035381:TATA-Binding Protein Associated Factors; D035581:Transcription Factor TFIIB; D035362:Transcription Factor TFIID; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D051548:Histone Acetyltransferases; C069001:TATA-binding protein associated factor 250 kDa; D012319:RNA Polymerase II