TAp73 contributes to the oxidative stress response by regulating protein synthesis

Alberto Marini, Barak Rotblat, Thomas Sbarrato, Maria Victoria Niklison-Chirou, John R.P. Knight, Kate Dudek, Carolyn Jones, Martin Bushell, Richard A. Knight, Ivano Amelio, Anne E. Willis, Gerry Melino

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

TAp73 is a transcription factor that plays key roles in brain development, aging, and cancer. At the cellular level, TAp73 is a critical homeostasis-maintaining factor, particularly following oxidative stress. Although major studies focused on TAp73 transcriptional activities have indicated a contribution of TAp73 to cellularmetabolism, the mechanisms underlying its role in redox homeostasis have not been completely elucidated. Here we show that TAp73 contributes to the oxidative stress response by participating in the control of protein synthesis. Regulation of mRNA translation occupies a central position in cellular homeostasis during the stress response, often by reducing global rates of protein synthesis and promoting translation of specific mRNAs. TAp73 depletion results in aberrant ribosomal RNA (rRNA) processing and impaired protein synthesis. In particular, polysomal profiles show that TAp73 promotes the integration of mRNAs that encode rRNA-processing factors in polysomes, supporting their translation. Concurrently, TAp73 depletion causes increased sensitivity to oxidative stress that correlates with reduced ATP levels, hyperactivation of AMPK, and translational defects. TAp73 is important for maintaining active translation of mitochondrial transcripts in response to oxidative stress, thus promoting mitochondrial activity. Our results indicate that TAp73 contributes to redox homeostasis by affecting the translational machinery, facilitating the translation of specific mitochondrial transcripts. This study identifies a mechanism by which TAp73 contributes to the oxidative stress response and describes a completely unexpected role for TAp73 in regulating protein synthesis.

Original languageEnglish
Pages (from-to)6219-6224
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number24
DOIs
Publication statusPublished - 12 Jun 2018

Keywords

  • Mitochondria
  • P53 family
  • ROS
  • TAp73
  • Translation

ASJC Scopus subject areas

  • General

Cite this

Marini, A., Rotblat, B., Sbarrato, T., Niklison-Chirou, M. V., Knight, J. R. P., Dudek, K., Jones, C., Bushell, M., Knight, R. A., Amelio, I., Willis, A. E., & Melino, G. (2018). TAp73 contributes to the oxidative stress response by regulating protein synthesis. Proceedings of the National Academy of Sciences of the United States of America, 115(24), 6219-6224. https://doi.org/10.1073/pnas.1718531115