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Open Access

Acetylation of p53 stimulates miRNA processing and determines cell survival following genotoxic stress

Jonathan Chang, Brandi N Davis‐Dusenbery, Risa Kashima, Xuan Jiang, Nisha Marathe, Roberto Sessa, Justin Louie, Wei Gu, Giorgio Lagna, Akiko Hata

Author Affiliations

  1. Jonathan Chang1,2,3,,
  2. Brandi N Davis‐Dusenbery2,,
  3. Risa Kashima1,,
  4. Xuan Jiang1,
  5. Nisha Marathe1,
  6. Roberto Sessa1,
  7. Justin Louie1,
  8. Wei Gu4,
  9. Giorgio Lagna1,2,5 and
  10. Akiko Hata*,1,2,3
  1. 1 Cardiovascular Research Institute, University of California, San Francisco, CA, USA
  2. 2 Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, USA
  3. 3 Department of Biochemistry, Tufts University School of Medicine, Boston, MA, USA
  4. 4 Department of Pathology and Cell Biology, Institute of Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, NY, USA
  5. 5 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA
  1. *Corresponding author. Cardiovascular Research Institute, University of California, San Francisco, 555 Mission Bay Boulevard South, Room 252T, San Francisco, CA 94158‐9001, USA. Tel.:+1 415 476 9758; Fax:+1 415 514 1173; E-mail: akiko.hata{at}ucsf.edu
  1. These authors contributed equally to this work.

Abstract

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.

  • Received April 18, 2013.
  • Accepted October 7, 2013.

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