The effect of inhibition of nucleotide synthesis on ribosome biogenesis and the induction of p53

[ENG] Ribosome biogenesis is one of the most energy consuming anabolic processes in a cell, required for the generation of the translational machinery to grow and proliferate. Moreover, this process necessitates the coordination of protein and nucleotide synthesis to generate ribosomal proteins (RPs...

Descripción completa

Detalles Bibliográficos
Autor: Riaño Canalias, Ferran
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2017
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/118701
Acceso en línea:https://hdl.handle.net/2445/118701
http://hdl.handle.net/10803/457972
Access Level:acceso abierto
Palabra clave:Oncologia
Càncer colorectal
Cicle cel·lular
Codi genètic
Oncology
Colorectal cancer
Cell cycle
Genetic code
Ribosomes
id ES_fd77b813df5ffb3fb09e1ba734f3ad4d
oai_identifier_str oai:diposit.ub.edu:2445/118701
network_acronym_str ES
network_name_str España
repository_id_str
spelling The effect of inhibition of nucleotide synthesis on ribosome biogenesis and the induction of p53Riaño Canalias, FerranOncologiaCàncer colorectalCicle cel·lularCodi genèticOncologyColorectal cancerCell cycleGenetic codeRibosomes[ENG] Ribosome biogenesis is one of the most energy consuming anabolic processes in a cell, required for the generation of the translational machinery to grow and proliferate. Moreover, this process necessitates the coordination of protein and nucleotide synthesis to generate ribosomal proteins (RPs) and ribosomal RNA (rRNA). Critically, increased rates of ribosome biogenesis are a hallmark of c-Myc driven CRC required to sustain exacerbated growth and proliferation, with recent studies showing that drugs that target ribosome biogenesis are clinically efficacious. We have previously shown that upon ribosome biogenesis impairment, a pre‐ribosomal complex formed by RPL11 and RPL5 and noncoding 5S rRNA is re‐directed from the incorporation into the pre-60S ribosome, to bind and inhibit HDM2, leading to p53 stabilization and cell cycle arrest. We have termed this response the Impaired Ribosome Biogenesis Checkpoint (IRBC). In this study I set out to analyze the effect of nucleotide depletion on ribosome biogenesis in c-Myc-driven CRC cell lines, addressing the role of the IRBC. Nucleotide depletion inhibited rRNA synthesis and elicited the IRBC, p53 stabilization, but failed to induce G1 cell cycle arrest as previously reported. I found that this was due to the loss of 5S RNA production, the limiting factor in triggering the IRBC, causing a disruption of the IRBC complex. Moreover, this allowed cells to escape G1 arrest and enter S phase, where they encountered replicative stress. These data support the hypothesis that in nucleotide deprived conditions the IRBC acts to hold cells in G1 to prevent them from replicating their DNA cells and eventually encountering genomic instability.Universitat de BarcelonaGentilella, AntonioThomas, GeorgeUniversitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació2017info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/118701http://hdl.handle.net/10803/457972Tesis Doctorals - Facultat - Farmàcia i Ciències de l'Alimentacióreponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglés(c) Riaño, 2017info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1187012026-05-27T06:46:51Z
dc.title.none.fl_str_mv The effect of inhibition of nucleotide synthesis on ribosome biogenesis and the induction of p53
title The effect of inhibition of nucleotide synthesis on ribosome biogenesis and the induction of p53
spellingShingle The effect of inhibition of nucleotide synthesis on ribosome biogenesis and the induction of p53
Riaño Canalias, Ferran
Oncologia
Càncer colorectal
Cicle cel·lular
Codi genètic
Oncology
Colorectal cancer
Cell cycle
Genetic code
Ribosomes
title_short The effect of inhibition of nucleotide synthesis on ribosome biogenesis and the induction of p53
title_full The effect of inhibition of nucleotide synthesis on ribosome biogenesis and the induction of p53
title_fullStr The effect of inhibition of nucleotide synthesis on ribosome biogenesis and the induction of p53
title_full_unstemmed The effect of inhibition of nucleotide synthesis on ribosome biogenesis and the induction of p53
title_sort The effect of inhibition of nucleotide synthesis on ribosome biogenesis and the induction of p53
dc.creator.none.fl_str_mv Riaño Canalias, Ferran
author Riaño Canalias, Ferran
author_facet Riaño Canalias, Ferran
author_role author
dc.contributor.none.fl_str_mv Gentilella, Antonio
Thomas, George
Universitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació
dc.subject.none.fl_str_mv Oncologia
Càncer colorectal
Cicle cel·lular
Codi genètic
Oncology
Colorectal cancer
Cell cycle
Genetic code
Ribosomes
topic Oncologia
Càncer colorectal
Cicle cel·lular
Codi genètic
Oncology
Colorectal cancer
Cell cycle
Genetic code
Ribosomes
description [ENG] Ribosome biogenesis is one of the most energy consuming anabolic processes in a cell, required for the generation of the translational machinery to grow and proliferate. Moreover, this process necessitates the coordination of protein and nucleotide synthesis to generate ribosomal proteins (RPs) and ribosomal RNA (rRNA). Critically, increased rates of ribosome biogenesis are a hallmark of c-Myc driven CRC required to sustain exacerbated growth and proliferation, with recent studies showing that drugs that target ribosome biogenesis are clinically efficacious. We have previously shown that upon ribosome biogenesis impairment, a pre‐ribosomal complex formed by RPL11 and RPL5 and noncoding 5S rRNA is re‐directed from the incorporation into the pre-60S ribosome, to bind and inhibit HDM2, leading to p53 stabilization and cell cycle arrest. We have termed this response the Impaired Ribosome Biogenesis Checkpoint (IRBC). In this study I set out to analyze the effect of nucleotide depletion on ribosome biogenesis in c-Myc-driven CRC cell lines, addressing the role of the IRBC. Nucleotide depletion inhibited rRNA synthesis and elicited the IRBC, p53 stabilization, but failed to induce G1 cell cycle arrest as previously reported. I found that this was due to the loss of 5S RNA production, the limiting factor in triggering the IRBC, causing a disruption of the IRBC complex. Moreover, this allowed cells to escape G1 arrest and enter S phase, where they encountered replicative stress. These data support the hypothesis that in nucleotide deprived conditions the IRBC acts to hold cells in G1 to prevent them from replicating their DNA cells and eventually encountering genomic instability.
publishDate 2017
dc.date.none.fl_str_mv 2017
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/118701
http://hdl.handle.net/10803/457972
url https://hdl.handle.net/2445/118701
http://hdl.handle.net/10803/457972
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv (c) Riaño, 2017
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Riaño, 2017
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv Tesis Doctorals - Facultat - Farmàcia i Ciències de l'Alimentació
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869425542447497216
score 15,301603

Similares en LA Referencia