In vivo reduction of RAD51-mediated homologous recombination triggers aging but impairs oncogenesis Journal Article
| Authors: | Matos-Rodrigues, G.; Barroca, V.; Muhammad, A. A.; Dardillac, E.; Allouch, A.; Koundrioukoff, S.; Lewandowski, D.; Despras, E.; Guirouilh-Barbat, J.; Frappart, L.; Kannouche, P.; Dupaigne, P.; Le Cam, E.; Perfettini, J. L.; Romeo, P. H.; Debatisse, M.; Jasin, M.; Livera, G.; Martini, E.; Lopez, B. S. |
| Article Title: | In vivo reduction of RAD51-mediated homologous recombination triggers aging but impairs oncogenesis |
| Abstract: | 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. © 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license. |
| Keywords: | adult; controlled study; genetics; nonhuman; protein function; neoplasm; neoplasms; animal cell; mouse; phenotype; animal; metabolism; animals; mice; animal tissue; dna damage; homologous recombination; dna repair; breast cancer; tumor volume; embryo; animal experiment; animal model; in vivo study; antineoplastic activity; enzyme activity; carcinogenesis; stem cell; tumorigenesis; cell transformation, neoplastic; aging; homeostasis; breast carcinogenesis; rad51 protein; rad51 recombinase; mouse model; rad51; female; article; neoplastic cell transformation |
| Journal Title: | EMBO Journal |
| Volume: | 42 |
| Issue: | 20 |
| ISSN: | 0261-4189 |
| Publisher: | Wiley Blackwell |
| Date Published: | 2023-10-16 |
| Start Page: | e110844 |
| Language: | English |
| DOI: | 10.15252/embj.2022110844 |
| PUBMED: | 37661798 |
| PROVIDER: | scopus |
| PMCID: | PMC10577633 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
