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We observed a general reduction in the expression of spliceosome components and splicing regulators in human cell lines undergoing replicative, stress\u2010induced, and telomere uncapping\u2010induced senescence. Supporting the view that defective splicing contributes to senescence, splicing inhibitors herboxidiene, and pladienolide B induced senescence in normal and cancer cell lines. Furthermore, depleting individual spliceosome components also promoted senescence. All senescence types were associated with an alternative splicing transition from the <jats:italic>MDM4\u2010FL<\/jats:italic> variant to <jats:italic>MDM4\u2010S<\/jats:italic>. The <jats:italic>MDM4<\/jats:italic> splicing shift was reproduced when splicing was inhibited, and spliceosome components were depleted. While decreasing the level of endogenous <jats:italic>MDM4<\/jats:italic> promoted senescence and cell survival independently of the <jats:italic>MDM4\u2010S<\/jats:italic> expression status, cell survival was also improved by increasing <jats:italic>MDM4\u2010S<\/jats:italic>. Overall, our work establishes that splicing defects modulate the alternative splicing of <jats:italic>MDM4<\/jats:italic> to promote senescence and cell survival.<\/jats:p>","DOI":"10.1111\/acel.14301","type":"journal-article","created":{"date-parts":[[2024,8,9]],"date-time":"2024-08-09T05:07:20Z","timestamp":1723180040000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A defective splicing machinery promotes senescence through MDM4 alternative splicing"],"prefix":"10.1111","volume":"23","author":[{"given":"Mathieu","family":"Desch\u00eanes","sequence":"first","affiliation":[{"name":"Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences Universit\u00e9 de Sherbrooke  Sherbrooke Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathieu","family":"Durand","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Infectious 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