In vivo inactivation of RAD51-mediated homologous recombination leads to premature aging, but not to tumorigenesis - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Pré-Publication, Document De Travail (Preprint/Prepublication) Année : 2022

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

Stéphane Koundrioukoff
  • Fonction : Auteur
  • PersonId : 1273834
Emmanuelle Despras
Josée Guirouilh-Barbat
Patricia L Kannouche
Michelle Debatisse
Maria Jasin
Bernard Lopez

Résumé

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.
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hal-03860785 , version 1 (18-11-2022)

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Gabriel Matos-Rodrigues, Vilma Barroca, Ali-Akbar Muhammad, Awatef Allouch, Stéphane Koundrioukoff, et al.. In vivo inactivation of RAD51-mediated homologous recombination leads to premature aging, but not to tumorigenesis. 2022. ⟨hal-03860785⟩
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