Inhibition of post-transcriptional steps in ribosome biogenesis confers cytoprotection against chemotherapeutic agents in a p53-dependent manner

Abstract The p53-mediated nucleolar stress response associated with inhibition of ribosomal RNA transcription was previously shown to potentiate killing of tumor cells. Here, we asked whether targeting of ribosome biogenesis can be used as the basis for selective p53-dependent cytoprotection of nonm...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Russell T. Sapio, Anastasiya N. Nezdyur, Matthew Krevetski, Leonid Anikin, Vincent J. Manna, Natalie Minkovsky, Dimitri G. Pestov
Formato: article
Lenguaje:EN
Publicado: Nature Portfolio 2017
Materias:
R
Q
Acceso en línea:https://doaj.org/article/5f32b7cad4d346218524d5760ba81655
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:5f32b7cad4d346218524d5760ba81655
record_format dspace
spelling oai:doaj.org-article:5f32b7cad4d346218524d5760ba816552021-12-02T16:07:58ZInhibition of post-transcriptional steps in ribosome biogenesis confers cytoprotection against chemotherapeutic agents in a p53-dependent manner10.1038/s41598-017-09002-w2045-2322https://doaj.org/article/5f32b7cad4d346218524d5760ba816552017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-09002-whttps://doaj.org/toc/2045-2322Abstract The p53-mediated nucleolar stress response associated with inhibition of ribosomal RNA transcription was previously shown to potentiate killing of tumor cells. Here, we asked whether targeting of ribosome biogenesis can be used as the basis for selective p53-dependent cytoprotection of nonmalignant cells. Temporary functional inactivation of the 60S ribosome assembly factor Bop1 in a 3T3 cell model markedly increased cell recovery after exposure to camptothecin or methotrexate. This was due, at least in part, to reversible pausing of the cell cycle preventing S phase associated DNA damage. Similar cytoprotective effects were observed after transient shRNA-mediated silencing of Rps19, but not several other tested ribosomal proteins, indicating distinct cellular responses to the inhibition of different steps in ribosome biogenesis. By temporarily inactivating Bop1 function, we further demonstrate selective killing of p53-deficient cells with camptothecin while sparing isogenic p53-positive cells. Thus, combining cytotoxic treatments with inhibition of select post-transcriptional steps of ribosome biogenesis holds potential for therapeutic targeting of cells that have lost p53.Russell T. SapioAnastasiya N. NezdyurMatthew KrevetskiLeonid AnikinVincent J. MannaNatalie MinkovskyDimitri G. PestovNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Russell T. Sapio
Anastasiya N. Nezdyur
Matthew Krevetski
Leonid Anikin
Vincent J. Manna
Natalie Minkovsky
Dimitri G. Pestov
Inhibition of post-transcriptional steps in ribosome biogenesis confers cytoprotection against chemotherapeutic agents in a p53-dependent manner
description Abstract The p53-mediated nucleolar stress response associated with inhibition of ribosomal RNA transcription was previously shown to potentiate killing of tumor cells. Here, we asked whether targeting of ribosome biogenesis can be used as the basis for selective p53-dependent cytoprotection of nonmalignant cells. Temporary functional inactivation of the 60S ribosome assembly factor Bop1 in a 3T3 cell model markedly increased cell recovery after exposure to camptothecin or methotrexate. This was due, at least in part, to reversible pausing of the cell cycle preventing S phase associated DNA damage. Similar cytoprotective effects were observed after transient shRNA-mediated silencing of Rps19, but not several other tested ribosomal proteins, indicating distinct cellular responses to the inhibition of different steps in ribosome biogenesis. By temporarily inactivating Bop1 function, we further demonstrate selective killing of p53-deficient cells with camptothecin while sparing isogenic p53-positive cells. Thus, combining cytotoxic treatments with inhibition of select post-transcriptional steps of ribosome biogenesis holds potential for therapeutic targeting of cells that have lost p53.
format article
author Russell T. Sapio
Anastasiya N. Nezdyur
Matthew Krevetski
Leonid Anikin
Vincent J. Manna
Natalie Minkovsky
Dimitri G. Pestov
author_facet Russell T. Sapio
Anastasiya N. Nezdyur
Matthew Krevetski
Leonid Anikin
Vincent J. Manna
Natalie Minkovsky
Dimitri G. Pestov
author_sort Russell T. Sapio
title Inhibition of post-transcriptional steps in ribosome biogenesis confers cytoprotection against chemotherapeutic agents in a p53-dependent manner
title_short Inhibition of post-transcriptional steps in ribosome biogenesis confers cytoprotection against chemotherapeutic agents in a p53-dependent manner
title_full Inhibition of post-transcriptional steps in ribosome biogenesis confers cytoprotection against chemotherapeutic agents in a p53-dependent manner
title_fullStr Inhibition of post-transcriptional steps in ribosome biogenesis confers cytoprotection against chemotherapeutic agents in a p53-dependent manner
title_full_unstemmed Inhibition of post-transcriptional steps in ribosome biogenesis confers cytoprotection against chemotherapeutic agents in a p53-dependent manner
title_sort inhibition of post-transcriptional steps in ribosome biogenesis confers cytoprotection against chemotherapeutic agents in a p53-dependent manner
publisher Nature Portfolio
publishDate 2017
url https://doaj.org/article/5f32b7cad4d346218524d5760ba81655
work_keys_str_mv AT russelltsapio inhibitionofposttranscriptionalstepsinribosomebiogenesisconferscytoprotectionagainstchemotherapeuticagentsinap53dependentmanner
AT anastasiyannezdyur inhibitionofposttranscriptionalstepsinribosomebiogenesisconferscytoprotectionagainstchemotherapeuticagentsinap53dependentmanner
AT matthewkrevetski inhibitionofposttranscriptionalstepsinribosomebiogenesisconferscytoprotectionagainstchemotherapeuticagentsinap53dependentmanner
AT leonidanikin inhibitionofposttranscriptionalstepsinribosomebiogenesisconferscytoprotectionagainstchemotherapeuticagentsinap53dependentmanner
AT vincentjmanna inhibitionofposttranscriptionalstepsinribosomebiogenesisconferscytoprotectionagainstchemotherapeuticagentsinap53dependentmanner
AT natalieminkovsky inhibitionofposttranscriptionalstepsinribosomebiogenesisconferscytoprotectionagainstchemotherapeuticagentsinap53dependentmanner
AT dimitrigpestov inhibitionofposttranscriptionalstepsinribosomebiogenesisconferscytoprotectionagainstchemotherapeuticagentsinap53dependentmanner
_version_ 1718384657776508928