Prieto, IgnacioZambrano, AlbertoLaso, JavierAranda, AnaSamper, EnriqueMonsalve, María2021-05-122021-05-122019Free Radic Biol Med. 2019 Jul;138:23-32.http://hdl.handle.net/20.500.12105/12946Aims: Oxidative stress is known to induce early replicative senescence. Senescence has been proposed to work as a barrier to immortalization and tumor development. Here, we aimed to evaluate the impact of the loss of peroxisome proliferator activated receptor γ co-activator 1α (PGC-1α), a master regulator of oxidative metabolism and mitochondrial reactive oxygen species (ROS) generation, on replicative senescence and immortalization in mouse embryonic fibroblasts (MEFs). Results: We found that primary MEFs lacking PGC-1α showed higher levels of ROS than wild-type MEFs at all cell passages tested. The elevated production of ROS was associated with higher levels of oxidative DNA damage and the increased formation of DNA double-strand breaks. Evaluation of the induction of DNA repair systems in response to γ-radiation indicated that the loss of PGC-1α also resulted in a small but significant reduction in their activity. DNA damage induced the early activation of senescence markers, including an increase in the number of β-galactosidase-positive cells, the induction of p53 phosphorylation, and the increase in p16 and p19 protein. These changes were, however, not sufficient to reduce proliferation rates of PGC-1α-deficient MEFs at any cell passage tested. Moreover, PGC-1α-deficient cells escaped replicative senescence. Innovation & conclusion: PGC-1α plays an important role in the control of cellular senescence and immortalization.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/ImmortalizationMitochondriaOxidative stressPGC-1αSenescenceDNA RepairAnimalsBiomarkersCell ProliferationCellular SenescenceCyclin-Dependent Kinase Inhibitor p16Cyclin-Dependent Kinase Inhibitor p19DNADNA Breaks, Double-StrandedEmbryo, MammalianFibroblastsGamma RaysGene Expression RegulationMiceMice, KnockoutMitochondriaOxidative StressPeroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alphaPhosphorylationReactive Oxygen SpeciesTumor Suppressor Protein p53Beta-GalactosidaseAttribution-NonCommercial-NoDerivatives 4.0 Internacional3102978713823-3210.1016/j.freeradbiomed.2019.04.0151873-4596Free Radical Biology & Medicineopen access