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Nucleophosmin modulates stability, activity, and nucleolar accumulation of base excision repair proteins

Nucleophosmin (NPM1) is a multifunctional protein that controls cell growth and genome stability via a mechanism that involves nucleolar–cytoplasmic shuttling. It is clear that NPM1 also contributes to the DNA damage response, yet its exact function is poorly understood. We recently linked NPM1 expr...

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Detalles Bibliográficos
Autores principales: Poletto, Mattia, Lirussi, Lisa, Wilson, David M., Tell, Gianluca
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019495/
https://www.ncbi.nlm.nih.gov/pubmed/24648491
http://dx.doi.org/10.1091/mbc.E13-12-0717
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author Poletto, Mattia
Lirussi, Lisa
Wilson, David M.
Tell, Gianluca
author_facet Poletto, Mattia
Lirussi, Lisa
Wilson, David M.
Tell, Gianluca
author_sort Poletto, Mattia
collection PubMed
description Nucleophosmin (NPM1) is a multifunctional protein that controls cell growth and genome stability via a mechanism that involves nucleolar–cytoplasmic shuttling. It is clear that NPM1 also contributes to the DNA damage response, yet its exact function is poorly understood. We recently linked NPM1 expression to the functional activation of the major abasic endonuclease in mammalian base excision repair (BER), apurinic/apyrimidinic endonuclease 1 (APE1). Here we unveil a novel role for NPM1 as a modulator of the whole BER pathway by 1) controlling BER protein levels, 2) regulating total BER capacity, and 3) modulating the nucleolar localization of several BER enzymes. We find that cell treatment with the genotoxin cisplatin leads to concurrent relocalization of NPM1 and BER components from nucleoli to the nucleoplasm, and cellular experiments targeting APE1 suggest a role for the redistribution of nucleolar BER factors in determining cisplatin toxicity. Finally, based on the use of APE1 as a representative protein of the BER pathway, our data suggest a function for BER proteins in the regulation of ribogenesis.
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spelling pubmed-40194952014-07-30 Nucleophosmin modulates stability, activity, and nucleolar accumulation of base excision repair proteins Poletto, Mattia Lirussi, Lisa Wilson, David M. Tell, Gianluca Mol Biol Cell Articles Nucleophosmin (NPM1) is a multifunctional protein that controls cell growth and genome stability via a mechanism that involves nucleolar–cytoplasmic shuttling. It is clear that NPM1 also contributes to the DNA damage response, yet its exact function is poorly understood. We recently linked NPM1 expression to the functional activation of the major abasic endonuclease in mammalian base excision repair (BER), apurinic/apyrimidinic endonuclease 1 (APE1). Here we unveil a novel role for NPM1 as a modulator of the whole BER pathway by 1) controlling BER protein levels, 2) regulating total BER capacity, and 3) modulating the nucleolar localization of several BER enzymes. We find that cell treatment with the genotoxin cisplatin leads to concurrent relocalization of NPM1 and BER components from nucleoli to the nucleoplasm, and cellular experiments targeting APE1 suggest a role for the redistribution of nucleolar BER factors in determining cisplatin toxicity. Finally, based on the use of APE1 as a representative protein of the BER pathway, our data suggest a function for BER proteins in the regulation of ribogenesis. The American Society for Cell Biology 2014-05-15 /pmc/articles/PMC4019495/ /pubmed/24648491 http://dx.doi.org/10.1091/mbc.E13-12-0717 Text en © 2014 Poletto et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Poletto, Mattia
Lirussi, Lisa
Wilson, David M.
Tell, Gianluca
Nucleophosmin modulates stability, activity, and nucleolar accumulation of base excision repair proteins
title Nucleophosmin modulates stability, activity, and nucleolar accumulation of base excision repair proteins
title_full Nucleophosmin modulates stability, activity, and nucleolar accumulation of base excision repair proteins
title_fullStr Nucleophosmin modulates stability, activity, and nucleolar accumulation of base excision repair proteins
title_full_unstemmed Nucleophosmin modulates stability, activity, and nucleolar accumulation of base excision repair proteins
title_short Nucleophosmin modulates stability, activity, and nucleolar accumulation of base excision repair proteins
title_sort nucleophosmin modulates stability, activity, and nucleolar accumulation of base excision repair proteins
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019495/
https://www.ncbi.nlm.nih.gov/pubmed/24648491
http://dx.doi.org/10.1091/mbc.E13-12-0717
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