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Article Dans Une Revue Scientific Reports Année : 2024

Lack of telomerase reduces cancer incidence and increases lifespan of zebrafish tp53M214K mutants

Résumé

Abstract Telomerase activity is restricted in humans and telomere attrition occurs in several tissues accompanying natural aging. Critically short telomeres trigger DNA damage responses and activate p53 which leads to apoptosis or replicative senescence. These processes reduce cell proliferation and disrupt tissue homeostasis, thus contributing to systemic aging. Similarly, zebrafish have restricted telomerase expression, and telomeres shorten to critical length during their lifespan. Telomerase-deficient zebrafish ( tert −/− ) is a premature model of aging that anticipates aging phenotypes due to early telomere shortening. tert −/− zebrafish have impaired cell proliferation, accumulation of DNA damage markers and p53 response. These cellular defects lead to disruption of tissue homeostasis, resulting in premature infertility, gastrointestinal atrophy, sarcopenia and kyphosis. Such consequences contribute to its premature death. Here we reveal a genetic interdependence between tp53 and telomerase function. Mutation of tp53 abrogates premature aging of tert −/− zebrafish, prolonging male fertility and lifespan. However, it does not fully rescue healthspan. tp53mut tert −/− zebrafish retain high levels of inflammation and increased spontaneous cancer incidence. Conversely, loss of telomerase prolongs the lifespan of tp53mut single mutants. Lack of telomerase reduces two-fold the cancer incidence in double mutants and increases lifetime survival. Thus, we observe a reciprocal rescue of tp53mut and tert −/− that ameliorates lifespan but not spontaneous cancer incidence of tp53mut , likely due to higher levels of inflammation.
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Dates et versions

hal-04490512 , version 1 (05-03-2024)

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Naz Şerifoğlu, Bruno Lopes-Bastos, Miguel Godinho Ferreira. Lack of telomerase reduces cancer incidence and increases lifespan of zebrafish tp53M214K mutants. Scientific Reports, 2024, 14 (1), pp.5382. ⟨10.1038/s41598-024-56153-8⟩. ⟨hal-04490512⟩
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