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In vivo inactivation of RAD51-mediated homologous recombination leads to premature aging, but not to tumorigenesis

Gabriel Matos-Rodrigues, Vilma Barroca, Ali-Akbar Muhammad, Awatef Allouch, Stephane Koundrioukoff, Daniel Lewandowski, Emmanuelle Despras, Josée Guirouilh-Barbat, Lucien Frappart, Patricia Kannouche, Pauline Dupaigne, Eric Le Cam, Jean-Luc Perfettini, Paul-Henri Romeo, Michelle Debatisse, Maria Jasin, Gabriel Livera, Emmanuelle Martini, View ORCID ProfileBernard S. Lopez
doi: https://doi.org/10.1101/2022.01.17.476609
Gabriel Matos-Rodrigues
1Université de Paris, INSERM U1016, UMR 8104 CNRS, Institut Cochin, Equipe Labellisée Ligue Contre le Cancer, Paris, France
2Université de Paris and Université Paris-Saclay, Laboratory of Development of the Gonads, IRCM/IBFJ CEA, UMR Genetic Stability Stem cells and Radiations, F-92265 Fontenay aux Roses, France
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Vilma Barroca
3Université de Paris and Université Paris-Saclay, Inserm, IRCM/IBFJ CEA, UMR Genetic Stability Stem cells and Radiations, F-92265 Fontenay aux Roses, France
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Ali-Akbar Muhammad
4Genome Maintenance and Molecular Microscopy UMR8126 CNRS, Université Paris-Sud, Université Paris-Saclay, Gustave Roussy, F-94805, Villejuif Cedex, France
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Awatef Allouch
5Cell Death and Aging Team, INSERM U1030, Laboratory of Molecular Radiotherapy. University Paris-Sud and Gustave Roussy. F-94805 Villejuif, France
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Stephane Koundrioukoff
6CNRS UMR8200 Sorbonne Universités, UPMC University, Paris, and Institut Gustave Roussy, F-94805 Villejuif, France
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Daniel Lewandowski
3Université de Paris and Université Paris-Saclay, Inserm, IRCM/IBFJ CEA, UMR Genetic Stability Stem cells and Radiations, F-92265 Fontenay aux Roses, France
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Emmanuelle Despras
7CNRS UMR8200, Laboratory of Genetic Instability and Oncogenesis. University Paris-Sud and Gustave Roussy. F-94805 Villejuif, France
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Josée Guirouilh-Barbat
1Université de Paris, INSERM U1016, UMR 8104 CNRS, Institut Cochin, Equipe Labellisée Ligue Contre le Cancer, Paris, France
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Lucien Frappart
8Leibniz Institute on Aging-Fritz Lipmann Institute, Jena, Germany
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Patricia Kannouche
7CNRS UMR8200, Laboratory of Genetic Instability and Oncogenesis. University Paris-Sud and Gustave Roussy. F-94805 Villejuif, France
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Pauline Dupaigne
4Genome Maintenance and Molecular Microscopy UMR8126 CNRS, Université Paris-Sud, Université Paris-Saclay, Gustave Roussy, F-94805, Villejuif Cedex, France
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Eric Le Cam
4Genome Maintenance and Molecular Microscopy UMR8126 CNRS, Université Paris-Sud, Université Paris-Saclay, Gustave Roussy, F-94805, Villejuif Cedex, France
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Jean-Luc Perfettini
5Cell Death and Aging Team, INSERM U1030, Laboratory of Molecular Radiotherapy. University Paris-Sud and Gustave Roussy. F-94805 Villejuif, France
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Paul-Henri Romeo
3Université de Paris and Université Paris-Saclay, Inserm, IRCM/IBFJ CEA, UMR Genetic Stability Stem cells and Radiations, F-92265 Fontenay aux Roses, France
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Michelle Debatisse
6CNRS UMR8200 Sorbonne Universités, UPMC University, Paris, and Institut Gustave Roussy, F-94805 Villejuif, France
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Maria Jasin
9Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
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Gabriel Livera
2Université de Paris and Université Paris-Saclay, Laboratory of Development of the Gonads, IRCM/IBFJ CEA, UMR Genetic Stability Stem cells and Radiations, F-92265 Fontenay aux Roses, France
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Emmanuelle Martini
2Université de Paris and Université Paris-Saclay, Laboratory of Development of the Gonads, IRCM/IBFJ CEA, UMR Genetic Stability Stem cells and Radiations, F-92265 Fontenay aux Roses, France
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  • For correspondence: emmanuelle.martini@cea.fr bernard.lopez@inserm.fr
Bernard S. Lopez
1Université de Paris, INSERM U1016, UMR 8104 CNRS, Institut Cochin, Equipe Labellisée Ligue Contre le Cancer, Paris, France
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  • ORCID record for Bernard S. Lopez
  • For correspondence: emmanuelle.martini@cea.fr bernard.lopez@inserm.fr
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Abstract

Genetic instability is a hallmark of both cancer and aging. Homologous recombination (HR) is a prominent DNA repair pathway maintaining genomic integrity. Mutations in many HR genes lead to cancer predisposition. Paradoxically, the consequences of mutations in the pivotal HR player, RAD51, on cancer development remain puzzling. Moreover, in contrast with other HR genes, RAD51 mouse models are not available to experimentally address the role of RAD51 on aging and carcinogenesis, in vivo. Here, we engineered a mouse model with an inducible dominant negative form of RAD51 (SMRad51) that suppresses RAD51-mediated HR without stimulating alternative non-conservative repair pathways. We found that, in vivo expression of SMRad51 did not trigger tumorigenesis, but instead induced premature aging. We propose that these in vivo phenotypes result from the exhaustion of proliferating progenitors submitted to chronic endogenous replication stress resulting from RAD51-mediated HR suppression. Our data underline the importance of the RAD51 activity for progenitors homeostasis, preventing aging, and more generally for the balance between cancer and aging.

Competing Interest Statement

The authors have declared no competing interest.

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Posted January 17, 2022.
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In vivo inactivation of RAD51-mediated homologous recombination leads to premature aging, but not to tumorigenesis
Gabriel Matos-Rodrigues, Vilma Barroca, Ali-Akbar Muhammad, Awatef Allouch, Stephane Koundrioukoff, Daniel Lewandowski, Emmanuelle Despras, Josée Guirouilh-Barbat, Lucien Frappart, Patricia Kannouche, Pauline Dupaigne, Eric Le Cam, Jean-Luc Perfettini, Paul-Henri Romeo, Michelle Debatisse, Maria Jasin, Gabriel Livera, Emmanuelle Martini, Bernard S. Lopez
bioRxiv 2022.01.17.476609; doi: https://doi.org/10.1101/2022.01.17.476609
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In vivo inactivation of RAD51-mediated homologous recombination leads to premature aging, but not to tumorigenesis
Gabriel Matos-Rodrigues, Vilma Barroca, Ali-Akbar Muhammad, Awatef Allouch, Stephane Koundrioukoff, Daniel Lewandowski, Emmanuelle Despras, Josée Guirouilh-Barbat, Lucien Frappart, Patricia Kannouche, Pauline Dupaigne, Eric Le Cam, Jean-Luc Perfettini, Paul-Henri Romeo, Michelle Debatisse, Maria Jasin, Gabriel Livera, Emmanuelle Martini, Bernard S. Lopez
bioRxiv 2022.01.17.476609; doi: https://doi.org/10.1101/2022.01.17.476609

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