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p53-Induced Apoptosis is Specified by a Translation Program Regulated by PCBP2 and DHX30

51 Pages Posted: 7 Oct 2019 Sneak Peek Status: Review Complete

See all articles by Dario Rizzotto

Dario Rizzotto

University of Trento - Department of Cellular, Computational and Integrative Biology

Sara Zaccara

University of Trento - Department of Cellular, Computational and Integrative Biology

Annalisa Rossi

University of Trento - Department of Cellular, Computational and Integrative Biology

Matthew D. Galbraith

University of Colorado at Denver - Linda Crnic Institute for Down Syndrome

Zdenek Andrysik

University of Colorado at Denver - Linda Crnic Institute for Down Syndrome

Ahwan Pandey

University of Colorado at Denver - Linda Crnic Institute for Down Syndrome

Kelly D. Sullivan

University of Colorado at Denver - Linda Crnic Institute for Down Syndrome

Alessandro Quattrone

University of Trento - Centre for Integrative Biology (CIBIO)

Joaquín M. Espinosa

University of Colorado at Denver - Linda Crnic Institute for Down Syndrome

Erik Dassi

University of Trento - Department of Cellular, Computational and Integrative Biology

Alberto Inga

University of Trento - Centre for Integrative Biology (CIBIO)

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Abstract

Activation of p53 by the small molecule Nutlin can result in a combination of cell cycle arrest and apoptosis. The relative strength of these events is difficult to predict by classical gene expression analysis, leaving uncertainty as to the therapeutic benefits of Nutlin. Here, we report a new translational control mechanism shaping p53-dependent apoptosis. Using polysome profiling, we establish Nutlin-induced apoptosis to be associated with the enhanced translation of mRNAs carrying multiple copies of a newly identified 3’UTR CG-rich motif mediating p53-dependent death (CGPD-motif). We identified PCBP2 and DHX30 as CGPD-motif interactors. We found that in cells undergoing persistent cell cycle arrest in response to Nutlin, CGPD-motif mRNAs are repressed by the PCBP2-dependent binding of DHX30 to the motif. Thus, upon DHX30 depletion in these cells, the translation of CGPD-motif mRNAs is increased, and the response to Nutlin shifts towards apoptosis. Instead, DHX30 inducible overexpression in SJSA1 cells, leads to decreased translation of CGPD-motif mRNAs. Overall, this work establishes the role of PCBP2-DHX30 in controlling the translation of CGPD-motif mRNAs and thus provide a new mechanism to modulate the induction of p53-dependent apoptosis.

Keywords: Nutlin, p53, DHX30, PCBP2, 3'UTR, polysomal profiling, translatome, apoptosis, translation, transcription

Suggested Citation

Rizzotto, Dario and Zaccara, Sara and Rossi, Annalisa and Galbraith, Matthew D. and Andrysik, Zdenek and Pandey, Ahwan and Sullivan, Kelly D. and Quattrone, Alessandro and Espinosa, Joaquín M. and Dassi, Erik and Inga, Alberto, p53-Induced Apoptosis is Specified by a Translation Program Regulated by PCBP2 and DHX30 (October 4, 2019). Available at SSRN: https://ssrn.com/abstract=3464029 or http://dx.doi.org/10.2139/ssrn.3464029
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Dario Rizzotto

University of Trento - Department of Cellular, Computational and Integrative Biology ( email )

Italy

Sara Zaccara

University of Trento - Department of Cellular, Computational and Integrative Biology ( email )

Italy

Annalisa Rossi

University of Trento - Department of Cellular, Computational and Integrative Biology ( email )

Italy

Matthew D. Galbraith

University of Colorado at Denver - Linda Crnic Institute for Down Syndrome ( email )

Building 500 - 13001 E. 17th Place, Campus Box C29
Aurora, CO 80045
United States

Zdenek Andrysik

University of Colorado at Denver - Linda Crnic Institute for Down Syndrome ( email )

Building 500 - 13001 E. 17th Place, Campus Box C29
Aurora, CO 80045
United States

Ahwan Pandey

University of Colorado at Denver - Linda Crnic Institute for Down Syndrome ( email )

Building 500 - 13001 E. 17th Place, Campus Box C29
Aurora, CO 80045
United States

Kelly D. Sullivan

University of Colorado at Denver - Linda Crnic Institute for Down Syndrome ( email )

Building 500 - 13001 E. 17th Place, Campus Box C29
Aurora, CO 80045
United States

Alessandro Quattrone

University of Trento - Centre for Integrative Biology (CIBIO)

via Sommarive n. 9, Povo (TN)
Povo, Trentino 38123
Italy

Joaquín M. Espinosa

University of Colorado at Denver - Linda Crnic Institute for Down Syndrome ( email )

Building 500 - 13001 E. 17th Place, Campus Box C29
Aurora, CO 80045
United States

Erik Dassi

University of Trento - Department of Cellular, Computational and Integrative Biology ( email )

Italy

Alberto Inga (Contact Author)

University of Trento - Centre for Integrative Biology (CIBIO)

via Sommarive n. 9, Povo (TN)
Povo, Trentino 38123
Italy

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