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How cells protect the nucleus from intracellular forces is poorly understood. Here, we show that the septin cytoskeleton buffers the actomyosin forces that have been shown to power nuclear movement. Septin filaments comprising SEPT9, a septin amplified in breast cancer, align with perinuclear actomyosin cables, which exhibit higher tensile stress during 3D confined migration through narrower pores. SEPT9 depletion amplifies actin stress during confined migration and after myosin II hyperactivation in nonmigrating cells causing actin and nuclear envelope ruptures. Following confined migration, DNA breaks, nuclear blebs, micronuclei, and cell death increase in SEPT9-depleted cells, phenotypes rescued by the oncogenic SEPT9 isoform 1. Clinicogenomic data reveal that SEPT9 amplification associates with lower genomic alteration in aggressive breast tumors. We propose that septins are a mechanoprotective element of the cytoskeleton, and SEPT9 amplification enhances tumor cell survival by preventing nuclear damage.<\/jats:p>","DOI":"10.1083\/jcb.202602074","type":"journal-article","created":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T13:20:47Z","timestamp":1792675247000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Septins buffer actomyosin forces to protect the nucleus from genotoxic mechanical stress"],"prefix":"10.1083","volume":"225","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0926-3336","authenticated-orcid":true,"given":"Franklin","family":"Mayca Pozo","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0153tk833","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Virginia School of Medicine 1 Department of Cell Biology, , Charlottesville, VA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0106-2812","authenticated-orcid":true,"given":"Sarah M.","family":"Butts","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0153tk833","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Virginia School of Medicine 1 Department of Cell Biology, , Charlottesville, VA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7214-3516","authenticated-orcid":true,"given":"Andrew W.","family":"Schaefer","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0153tk833","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Virginia School of Medicine 1 Department of Cell Biology, , Charlottesville, VA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2343-5851","authenticated-orcid":true,"given":"Cristina","family":"Montagna","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0060x3y55","id-type":"ROR","asserted-by":"publisher"}],"name":"Rutgers Cancer Institute of New Jersey 2 Department of Radiology and Oncology, , New Brunswick, NJ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1082-9763","authenticated-orcid":true,"given":"Elias T.","family":"Spiliotis","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0153tk833","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Virginia School of Medicine 1 Department of Cell Biology, , Charlottesville, VA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2026,10,22]]},"reference":[{"key":"2026102209201548200_bib1","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1038\/256597a0","article-title":"Phosphorylation of platelet myosin increases actin-activated myosin ATPase activity","volume":"256","author":"Adelstein","year":"1975","journal-title":"Nature"},{"key":"2026102209201548200_bib2","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1038\/s42003-024-06366-4","article-title":"Vimentin is a key regulator of cell mechanosensing through opposite actions on actomyosin and microtubule networks","volume":"7","author":"Alisafaei","year":"2024","journal-title":"Commun. 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