Senescence-associated ribosome biogenesis defects contributes to cell cycle arrest through the Rb pathway

Frédéric Lessard; Sebastian Igelmann; Christian Trahan; Geneviève Huot; Emmanuelle Saint-Germain; Lian Mignacca; Neylen Del Toro; Stéphane Lopes-Paciencia; Benjamin Le Calve; Marinieve Montero; Xavier Deschënes-Simard; Marina Bury; Olga Moiseeva; Marie-Camille Rowell; Marlene Oeffinger; Cornelia E. Zorca; Daniel Zenklusen; Léa Brakier-Gingras; Véronique Bourdeau; Gerardo Ferbeyre

doi:10.1038/s41556-018-0127-y

Senescence-associated ribosome biogenesis defects contributes to cell cycle arrest through the Rb pathway

Frédéric Lessard, Sebastian Igelmann, Christian Trahan, Geneviève Huot, Emmanuelle Saint-Germain, Lian Mignacca, Neylen Del Toro, Stéphane Lopes-Paciencia, Benjamin Le Calve, Marinieve Montero, Xavier Deschënes-Simard, Marina Bury, Olga Moiseeva, Marie-Camille Rowell, Marlene Oeffinger, Cornelia E. Zorca, Daniel Zenklusen, Léa Brakier-Gingras, Véronique Bourdeau, Gerardo Ferbeyre

Research output: Contribution to journal › Article › peer-review

Abstract

Cellular senescence is a tumour suppressor programme characterized by a stable cell cycle arrest. Here we report that cellular senescence triggered by a variety of stimuli leads to diminished ribosome biogenesis and the accumulation of both rRNA precursors and ribosomal proteins. These defects were associated with reduced expression of several ribosome biogenesis factors, the knockdown of which was also sufficient to induce senescence. Genetic analysis revealed that Rb but not p53 was required for the senescence response to altered ribosome biogenesis. Mechanistically, the ribosomal protein S14 (RPS14 or uS11) accumulates in the soluble non-ribosomal fraction of senescent cells, where it binds and inhibits CDK4 (cyclin-dependent kinase 4). Overexpression of RPS14 is sufficient to inhibit Rb phosphorylation, inducing cell cycle arrest and senescence. Here we describe a mechanism for maintaining the senescent cell cycle arrest that may be relevant for cancer therapy, as well as biomarkers to identify senescent cells.

Original language	English
Pages (from-to)	789-799
Number of pages	11
Journal	nature cell biology
Volume	20
Issue number	7
DOIs	https://doi.org/10.1038/s41556-018-0127-y
Publication status	Published - 1 Jul 2018

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10.1038/s41556-018-0127-y

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Lessard, F., Igelmann, S., Trahan, C., Huot, G., Saint-Germain, E., Mignacca, L., Del Toro, N., Lopes-Paciencia, S., Le Calve, B., Montero, M., Deschënes-Simard, X., Bury, M., Moiseeva, O., Rowell, M.-C., Oeffinger, M., Zorca, C. E., Zenklusen, D., Brakier-Gingras, L., Bourdeau, V., & Ferbeyre, G. (2018). Senescence-associated ribosome biogenesis defects contributes to cell cycle arrest through the Rb pathway. nature cell biology, 20(7), 789-799. https://doi.org/10.1038/s41556-018-0127-y

@article{b44ff10ebcc6419d9f9bcfc49f10a83a,

title = "Senescence-associated ribosome biogenesis defects contributes to cell cycle arrest through the Rb pathway",

abstract = "Cellular senescence is a tumour suppressor programme characterized by a stable cell cycle arrest. Here we report that cellular senescence triggered by a variety of stimuli leads to diminished ribosome biogenesis and the accumulation of both rRNA precursors and ribosomal proteins. These defects were associated with reduced expression of several ribosome biogenesis factors, the knockdown of which was also sufficient to induce senescence. Genetic analysis revealed that Rb but not p53 was required for the senescence response to altered ribosome biogenesis. Mechanistically, the ribosomal protein S14 (RPS14 or uS11) accumulates in the soluble non-ribosomal fraction of senescent cells, where it binds and inhibits CDK4 (cyclin-dependent kinase 4). Overexpression of RPS14 is sufficient to inhibit Rb phosphorylation, inducing cell cycle arrest and senescence. Here we describe a mechanism for maintaining the senescent cell cycle arrest that may be relevant for cancer therapy, as well as biomarkers to identify senescent cells.",

author = "Fr{\'e}d{\'e}ric Lessard and Sebastian Igelmann and Christian Trahan and Genevi{\`e}ve Huot and Emmanuelle Saint-Germain and Lian Mignacca and {Del Toro}, Neylen and St{\'e}phane Lopes-Paciencia and {Le Calve}, Benjamin and Marinieve Montero and Xavier Desch{\"e}nes-Simard and Marina Bury and Olga Moiseeva and Marie-Camille Rowell and Marlene Oeffinger and Zorca, {Cornelia E.} and Daniel Zenklusen and L{\'e}a Brakier-Gingras and V{\'e}ronique Bourdeau and Gerardo Ferbeyre",

note = "Funding Information: We thank D. P. Baker (Biogen Idec), D. A. Galloway (Fred Hutchinson Cancer Center), N. Bardeesy (MGH), S. Lowe (MSK), A. Koff (MSK), T. Moss (U. Laval), I. Topisirovic, P. Chartrand (U. Montr{\'e}al), V. Blank (McGill University) and B. Weinberg (MIT) for comments and/or reagents. We thank {\'E}. Bonneil, F. McManus and the IRIC Proteomics Core Facility for proteomic analysis. We thank J. Hinsinger, M. Birlea and the IRIC Histology Core Facility for immunohistochemistry. F.L. is supported by FRQS (Fonds de Recherche du Qu{\'e}bec-Sant{\'e}) and the CRS (Cancer Research Society). G.F. is supported by FRQS. Work was funded by grants from the CIHR (Canadian Institute of Health and Research: CIHR MOP11151) to G.F., (Canadian Institutes of Health Research: CIHR Funding Information: We thank D. P. Baker (Biogen Idec), D. A. Galloway (Fred Hutchinson Cancer Center), N. Bardeesy (MGH), S. Lowe (MSK), A. Koff (MSK), T. Moss (U. Laval), I. Topisirovic, P. Chartrand (U. Montr?al), V. Blank (McGill University) and B. Weinberg (MIT) for comments and/or reagents. We thank . Bonneil, F. McManus and the IRIC Proteomics Core Facility for proteomic analysis. We thank J. Hinsinger, M. Birlea and the IRIC Histology Core Facility for immunohistochemistry. F.L. is supported by FRQS (Fonds de Recherche du Qu?bec-Sant?) and the CRS (Cancer Research Society). G.F. is supported by FRQS. Work was funded by grants from the CIHR (Canadian Institute of Health and Research: CIHR MOP11151) to G.F., (Canadian Institutes of Health Research: CIHR MOP106628) to M.O. and the CCSRI (Canadian Cancer Society Research Institute: 704223) to G.F. Publisher Copyright: {\textcopyright} 2018 The Author(s). Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

year = "2018",

month = jul,

day = "1",

doi = "10.1038/s41556-018-0127-y",

language = "English",

volume = "20",

pages = "789--799",

journal = "nature cell biology",

issn = "1476-4679",

publisher = "Nature Publishing Group",

number = "7",

}

Lessard, F, Igelmann, S, Trahan, C, Huot, G, Saint-Germain, E, Mignacca, L, Del Toro, N, Lopes-Paciencia, S, Le Calve, B, Montero, M, Deschënes-Simard, X, Bury, M, Moiseeva, O, Rowell, M-C, Oeffinger, M, Zorca, CE, Zenklusen, D, Brakier-Gingras, L, Bourdeau, V & Ferbeyre, G 2018, 'Senescence-associated ribosome biogenesis defects contributes to cell cycle arrest through the Rb pathway', nature cell biology, vol. 20, no. 7, pp. 789-799. https://doi.org/10.1038/s41556-018-0127-y

TY - JOUR

T1 - Senescence-associated ribosome biogenesis defects contributes to cell cycle arrest through the Rb pathway

AU - Lessard, Frédéric

AU - Igelmann, Sebastian

AU - Trahan, Christian

AU - Huot, Geneviève

AU - Saint-Germain, Emmanuelle

AU - Mignacca, Lian

AU - Del Toro, Neylen

AU - Lopes-Paciencia, Stéphane

AU - Le Calve, Benjamin

AU - Montero, Marinieve

AU - Deschënes-Simard, Xavier

AU - Bury, Marina

AU - Moiseeva, Olga

AU - Rowell, Marie-Camille

AU - Oeffinger, Marlene

AU - Zorca, Cornelia E.

AU - Zenklusen, Daniel

AU - Brakier-Gingras, Léa

AU - Bourdeau, Véronique

AU - Ferbeyre, Gerardo

N1 - Funding Information: We thank D. P. Baker (Biogen Idec), D. A. Galloway (Fred Hutchinson Cancer Center), N. Bardeesy (MGH), S. Lowe (MSK), A. Koff (MSK), T. Moss (U. Laval), I. Topisirovic, P. Chartrand (U. Montréal), V. Blank (McGill University) and B. Weinberg (MIT) for comments and/or reagents. We thank É. Bonneil, F. McManus and the IRIC Proteomics Core Facility for proteomic analysis. We thank J. Hinsinger, M. Birlea and the IRIC Histology Core Facility for immunohistochemistry. F.L. is supported by FRQS (Fonds de Recherche du Québec-Santé) and the CRS (Cancer Research Society). G.F. is supported by FRQS. Work was funded by grants from the CIHR (Canadian Institute of Health and Research: CIHR MOP11151) to G.F., (Canadian Institutes of Health Research: CIHR Funding Information: We thank D. P. Baker (Biogen Idec), D. A. Galloway (Fred Hutchinson Cancer Center), N. Bardeesy (MGH), S. Lowe (MSK), A. Koff (MSK), T. Moss (U. Laval), I. Topisirovic, P. Chartrand (U. Montr?al), V. Blank (McGill University) and B. Weinberg (MIT) for comments and/or reagents. We thank . Bonneil, F. McManus and the IRIC Proteomics Core Facility for proteomic analysis. We thank J. Hinsinger, M. Birlea and the IRIC Histology Core Facility for immunohistochemistry. F.L. is supported by FRQS (Fonds de Recherche du Qu?bec-Sant?) and the CRS (Cancer Research Society). G.F. is supported by FRQS. Work was funded by grants from the CIHR (Canadian Institute of Health and Research: CIHR MOP11151) to G.F., (Canadian Institutes of Health Research: CIHR MOP106628) to M.O. and the CCSRI (Canadian Cancer Society Research Institute: 704223) to G.F. Publisher Copyright: © 2018 The Author(s). Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2018/7/1

Y1 - 2018/7/1

N2 - Cellular senescence is a tumour suppressor programme characterized by a stable cell cycle arrest. Here we report that cellular senescence triggered by a variety of stimuli leads to diminished ribosome biogenesis and the accumulation of both rRNA precursors and ribosomal proteins. These defects were associated with reduced expression of several ribosome biogenesis factors, the knockdown of which was also sufficient to induce senescence. Genetic analysis revealed that Rb but not p53 was required for the senescence response to altered ribosome biogenesis. Mechanistically, the ribosomal protein S14 (RPS14 or uS11) accumulates in the soluble non-ribosomal fraction of senescent cells, where it binds and inhibits CDK4 (cyclin-dependent kinase 4). Overexpression of RPS14 is sufficient to inhibit Rb phosphorylation, inducing cell cycle arrest and senescence. Here we describe a mechanism for maintaining the senescent cell cycle arrest that may be relevant for cancer therapy, as well as biomarkers to identify senescent cells.

AB - Cellular senescence is a tumour suppressor programme characterized by a stable cell cycle arrest. Here we report that cellular senescence triggered by a variety of stimuli leads to diminished ribosome biogenesis and the accumulation of both rRNA precursors and ribosomal proteins. These defects were associated with reduced expression of several ribosome biogenesis factors, the knockdown of which was also sufficient to induce senescence. Genetic analysis revealed that Rb but not p53 was required for the senescence response to altered ribosome biogenesis. Mechanistically, the ribosomal protein S14 (RPS14 or uS11) accumulates in the soluble non-ribosomal fraction of senescent cells, where it binds and inhibits CDK4 (cyclin-dependent kinase 4). Overexpression of RPS14 is sufficient to inhibit Rb phosphorylation, inducing cell cycle arrest and senescence. Here we describe a mechanism for maintaining the senescent cell cycle arrest that may be relevant for cancer therapy, as well as biomarkers to identify senescent cells.

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U2 - 10.1038/s41556-018-0127-y

DO - 10.1038/s41556-018-0127-y

M3 - Article

SN - 1476-4679

VL - 20

SP - 789

EP - 799

JO - nature cell biology

JF - nature cell biology

IS - 7

ER -

Senescence-associated ribosome biogenesis defects contributes to cell cycle arrest through the Rb pathway

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