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Article Dans Une Revue EMBO Journal Année : 2023

In vivo reduction of RAD51 ‐mediated homologous recombination triggers aging but impairs oncogenesis

Emmanuelle Despras
Josée Guirouilh-Barbat
Patricia L Kannouche
Pauline Dupaigne
Eric Le Cam
Maria Jasin
Bernard Lopez

Résumé

Homologous recombination (HR) is a prominent DNA repair pathway maintaining genome integrity. Mutations in many HR genes lead to cancer predisposition. Paradoxically, the implication of the pivotal HR factor RAD51 on cancer development remains puzzling. Particularly, no RAD51 mouse models are available to address the role of RAD51 in aging and carcinogenesis in vivo . We engineered a mouse model with an inducible dominant‐negative form of RAD51 ( SMRad51 ) that suppresses RAD51‐mediated HR without stimulating alternative mutagenic repair pathways. We found that in vivo expression of SMRad51 led to replicative stress, systemic inflammation, progenitor exhaustion, premature aging and reduced lifespan, but did not trigger tumorigenesis. Expressing SMRAD51 in a breast cancer predisposition mouse model (PyMT) decreased the number and the size of tumors, revealing an anti‐tumor activity of SMRAD51. We propose that these in vivo phenotypes result from chronic endogenous replication stress caused by HR decrease, which preferentially targets progenitors and tumor cells. Our work underlines the importance of RAD51 activity for progenitor cell homeostasis, preventing aging and more generally for the balance between cancer and aging.
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Dates et versions

hal-04256476 , version 1 (27-10-2023)

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Paternité - Pas d'utilisation commerciale - Pas de modification

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Gabriel Matos-Rodrigues, Vilma Barroca, Ali‐akbar Muhammad, Elodie Dardillac, Awatef Allouch, et al.. In vivo reduction of RAD51 ‐mediated homologous recombination triggers aging but impairs oncogenesis. EMBO Journal, 2023, 42 (20), pp.e110844. ⟨10.15252/embj.2022110844⟩. ⟨hal-04256476⟩
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