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However, the impact of S6 kinase activity on cellular senescence remains to be established. Here, we show that the constitutive activation of mammalian target of rapamycin complex 1 (mTORC1) by tuberous sclerosis complex (TSC) mutations induces a premature senescence programme in fibroblasts that relies on S6 kinases. To determine novel molecular targets linking S6 kinase activation to the control of senescence, we set up a chemical genetic screen, leading to the identification of the nuclear epigenetic factor ZRF1 (also known as DNAJC2, MIDA1, Mpp11). S6 kinases phosphorylate ZRF1 on Ser47 in cultured cells and in mammalian tissues\n                    <jats:italic>in\u00a0vivo<\/jats:italic>\n                    . Knock\u2010down of ZRF1 or expression of a phosphorylation mutant is sufficient to blunt the S6 kinase\u2010dependent senescence programme. This is traced by a sharp alteration in p16 levels, the cell cycle inhibitor and a master regulator of senescence. Our findings reveal a mechanism by which nutrient sensing pathways impact on cell senescence through the activation of mTORC1\u2010S6 kinases and the phosphorylation of ZRF1.\n                  <\/jats:p>","DOI":"10.15252\/embj.201694966","type":"journal-article","created":{"date-parts":[[2017,2,27]],"date-time":"2017-02-27T20:55:30Z","timestamp":1488228930000},"page":"736-750","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["ZRF1 is a novel S6 kinase substrate that drives the senescence programme"],"prefix":"10.1038","volume":"36","author":[{"given":"Manuela","family":"Barilari","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Bonfils","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Treins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vonda","family":"Koka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delphine","family":"De Villeneuve","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvie","family":"Fabrega","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7864-8937","authenticated-orcid":false,"given":"Mario","family":"Pende","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,2,27]]},"reference":[{"key":"BFEMBJ201694966_CR1","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/j.cmet.2007.05.006","volume":"5","author":"V Aguilar","year":"2007","unstructured":"Aguilar V, Alliouachene S, Sotiropoulos A, Sobering A, Athea Y, Djouadi F, Miraux S, Thiaudiere E, Foretz M, Viollet B, Diolez P, Bastin J, Benit P, Rustin P, Carling D, Sandri M, Ventura\u2010Clapier R, Pende M (2007) S6 kinase deletion suppresses muscle growth adaptations to nutrient availability by activating AMP kinase. 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