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Here, to address how cells overcome proliferation arrest imposed by centrosome amplification, we describe a genome-wide screen revealing that downregulation of the Wnt, Hippo, Tpr53, PIDDosome, ciliary biogenesis, or autophagy pathways enables proliferation of mouse embryonic stem cells having PLK4-mediated centrosome amplification. We select the tumor suppressor, Guanine-nucleotide Activating Protein ARHGAP15, for further study as its depletion activates autophagy, overcomes centrosome amplification, and enables embryonic fibroblast proliferation. Reduction of centrosomes following ARHGAP15 depletion requires autophagy protein, ATG16L1, which associates with ARHGAP15 when the autophagy pathway is inactive. ARHGAP15 is opposed by Guanine-nucleotide Exchange Factor ARHGEF2, which is activated by the centriolar protein CEP170 to generate RAC1-GTP and promote autophagy. Together our findings add extra dimensions to the roles of RAC1 in cytoskeletal regulation and ARHGAP15 as a potential tumor suppressor.<\/jats:p>","DOI":"10.1038\/s41467-026-74702-9","type":"journal-article","created":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T09:06:34Z","timestamp":1782032794000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Sensing centrosome amplification: the interface between centriole duplication and autophagy"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0614-7575","authenticated-orcid":false,"given":"Paula A.","family":"Coelho","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Fatalska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Geymonat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1725-0175","authenticated-orcid":false,"given":"Ramona","family":"Lattao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0956-0103","authenticated-orcid":false,"given":"David M.","family":"Glover","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,21]]},"reference":[{"key":"74702_CR1","first-page":"151","volume":"3","author":"Boveri","year":"1887","unstructured":"Boveri Ueber den Antheil des Spermatozoon an der Theilung des Eies. 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