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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,10,11]]},"abstract":"<jats:p>Aneuploidy, the incorrect number of whole chromosomes, is a common feature of tumors that contributes to their initiation and evolution. Preventing aneuploidy requires properly functioning kinetochores, which are large protein complexes assembled on centromeric DNA that link mitotic chromosomes to dynamic spindle microtubules and facilitate chromosome segregation. The kinetochore leverages at least two mechanisms to prevent aneuploidy: error correction and the spindle assembly checkpoint (SAC). BubR1, a factor involved in both processes, was identified as a cancer dependency and therapeutic target in multiple tumor types; however, it remains unclear what specific oncogenic pressures drive this enhanced dependency on BubR1 and whether it arises from BubR1\u2019s regulation of the SAC or error-correction pathways. Here, we use a genetically controlled transformation model and glioblastoma tumor isolates to show that constitutive signaling by RAS or MAPK is necessary for cancer-specific BubR1 vulnerability. The MAPK pathway enzymatically hyperstimulates a network of kinetochore kinases that compromises chromosome segregation, rendering cells more dependent on two BubR1 activities: counteracting excessive kinetochore\u2013microtubule turnover for error correction and maintaining the SAC. This work expands our understanding of how chromosome segregation adapts to different cellular states and reveals an oncogenic trigger of a cancer-specific defect.<\/jats:p>","DOI":"10.1073\/pnas.2208255119","type":"journal-article","created":{"date-parts":[[2022,10,3]],"date-time":"2022-10-03T15:17:41Z","timestamp":1664810261000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":23,"title":["Hyper-active RAS\/MAPK introduces cancer-specific mitotic vulnerabilities"],"prefix":"10.1073","volume":"119","author":[{"given":"Jacob A.","family":"Herman","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romario R.","family":"Romain","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pia","family":"Hoellerbauer","sequence":"additional","affiliation":[{"name":"Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6685-2586","authenticated-orcid":false,"given":"Hazheen K.","family":"Shirnekhi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David C.","family":"King","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith F.","family":"DeLuca","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4313-4573","authenticated-orcid":false,"given":"Erin","family":"Osborne Nishimura","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick J.","family":"Paddison","sequence":"additional","affiliation":[{"name":"Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3598-1721","authenticated-orcid":false,"given":"Jennifer G.","family":"DeLuca","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,10,3]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2004.1610"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2006.07.022"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1809"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3916"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2021.06.009"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.4161\/23723548.2014.970484"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/32688"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.142.1.1"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.146.5.941"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1382"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0401142101"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200208091"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2005.03.036"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1208"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-12-0353"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-03133-3"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-03114-6"},{"key":"e_1_3_4_18_2","first-page":"955","article-title":"Mechanisms of aneuploidy induction by RAS and RAF oncogenes","volume":"1","author":"Kamata T.","year":"2011","unstructured":"T. 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