Acetylation of p53 stimulates miRNA processing and determines cell survival following genotoxic stress.
It is widely accepted that different forms of stress activate a common target, p53, yet different outcomes are triggered in a stress-specific manner. For example, activation of p53 by genotoxic agents, such as camptothecin (CPT), triggers apoptosis, while non-genotoxic activation of p53 by Nutlin-3 (Nut3) leads to cell-cycle arrest without significant apoptosis. Such stimulus-specific responses are attributed to differential transcriptional activation of various promoters by p53. In this study, we demonstrate that CPT, but not Nut3, induces miR-203, which downregulates anti-apoptotic bcl-w and promotes cell death in a p53-dependent manner. We find that acetylation of K120 in the DNA-binding domain of p53 augments its association with the Drosha microprocessor and promotes nuclear primary miRNA processing. Knockdown of human orthologue of Males absent On the First (hMOF), the acetyltransferase that targets K120 in p53, abolishes induction of miR-203 and cell death mediated by CPT. Thus, this study reveals that p53 acetylation at K120 plays a critical role in the regulation of the Drosha microprocessor and that post-transcriptional regulation of gene expression by p53 via miRNAs plays a role in determining stress-specific cellular outcomes.
1] Cardiovascular Research Institute, University of California, San Francisco, CA, USA [2] Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, USA [3] Department of Biochemistry, Tufts University School of Medicine, Boston, MA, USA.
Jonathan
J
Chang
Brandi N
BN
Davis-Dusenbery
Risa
R
Kashima
Xuan
X
Jiang
Nisha
N
Marathe
Roberto
R
Sessa
Justin
J
Louie
Wei
W
Gu
Giorgio
G
Lagna
Akiko
0000000337841738
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Hata
D000107:Acetylation; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002166:Camptothecin / Q000494:pharmacology; D002470:Cell Survival / Q000235:genetics; D004249:DNA Damage; D045325:HCT116 Cells / Q000187:drug effects; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012323:RNA Processing, Post-Transcriptional; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C491073:BCL2L2 protein, human; D007093:Imidazoles; C546703:MIRN203 microRNA, human; D035683:MicroRNAs; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D051548:Histone Acetyltransferases; C496552:KAT8 protein, human; C517918:DROSHA protein, human; D043244:Ribonuclease III; D002166:Camptothecin