Humbert, NicolasNavaratnam, NaveenanAugert, ArnaudDa Costa, MarcoMartien, SébastienWang, JingMartinez Garcia, Maria DoloresAbbadie, CorinneCarling, Davidde Launoit, YvanGil, JesúsBernard, David2024-02-012024-02-012010-01-20EMBO J . 2010 ;29(2):376-86.http://hdl.handle.net/20.500.12105/17412Senescence is an irreversible cell-cycle arrest that is elicited by a wide range of factors, including replicative exhaustion. Emerging evidences suggest that cellular senescence contributes to ageing and acts as a tumour suppressor mechanism. To identify novel genes regulating senescence, we performed a loss-of-function screen on normal human diploid fibroblasts. We show that downregulation of the AMPK-related protein kinase 5 (ARK5 or NUAK1) results in extension of the cellular replicative lifespan. Interestingly, the levels of NUAK1 are upregulated during senescence whereas its ectopic expression triggers a premature senescence. Cells that constitutively express NUAK1 suffer gross aneuploidies and show diminished expression of the genomic stability regulator LATS1, whereas depletion of NUAK1 with shRNA exerts opposite effects. Interestingly, a dominant-negative form of LATS1 phenocopies NUAK1 effects. Moreover, we show that NUAK1 phosphorylates LATS1 at S464 and this has a role in controlling its stability. In summary, our work highlights a novel role for NUAK1 in the control of cellular senescence and cellular ploidy.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Cellular SenescencePloidiesAMP-Activated Protein Kinase KinasesCell LineFibroblastsGene Expression RegulationHumansPhosphorylationProtein KinasesProtein Serine-Threonine KinasesRepressor ProteinsAttribution-NonCommercial-NoDerivatives 4.0 Internacional1992712729237610.1038/emboj.2009.3421460-2075The EMBO journalopen access