Vitamin D3 ameliorates R-loop-induced replication stress and chromosomal instability in MED12-mutant uterine fibroids

Vitamin D3 ameliorates R-loop-induced replication stress and chromosomal instability in MED12-mutant uterine fibroids | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Vitamin D3 ameliorates R-loop-induced replication stress and chromosomal instability in MED12-mutant uterine fibroids Sribalasubashini Muralimanoharan, Ana Corachán, Azad Khosh, Sierra Hathaway, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8031602/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Uterine fibroids (UFs) are the most important benign neoplastic threat to women’s health worldwide, with no long-term noninvasive treatment options currently available. Among known UF driver alterations, somatic mutations in Mediator subunit MED12 are by the far the most prevalent, accounting for up to 80% of these clinically significant lesions. Although it is presently unclear how MED12 mutations trigger neoplastic transformation, MED12-mutant UFs are nonetheless characterized by significant chromosomal loss and rearrangement, suggesting genomic instability as a driving force in tumor development. However, the basis by which MED12 mutations drive genomic instability is not known. Herein, we show that R-loop-driven replication stress in MED12-mutant UFs leads to DNA under-replication and mitotic segregation errors that drive chromosomal instability. Notably, we find that vitamin D3 (VD3), a modifiable risk factor in UF development, suppresses pathogenic R-loop accrual and ameliorates replication stress-driven chromosomal instability, contributing to growth inhibition of patient-derived MED12-mutant UF xenografts in vivo. Altogether these findings uncover a molecular basis by which the predominant UF driver converges with a known risk factor at the interface of genomic instability, with significant translational implications for personalized UF prevention and treatment. Biological sciences/Cancer Health sciences/Diseases Biological sciences/Genetics Biological sciences/Molecular biology Health sciences/Molecular medicine Health sciences/Oncology Full Text Additional Declarations No competing interests reported. Supplementary Files MuralimanoharanetalFinal09122025SuppMaterial.docx TableS3DCL0.3DownvsCTL.xlsx TableS2VD30.5DownvsCTL.xlsx MuralimanoharanetalRevisedsupp112025.pdf TableS3Individualtumormeasurementsperanimal.xlsx TableS7Bodyweightpercentagechangeinmousemodel.xlsx TableS6Bodyweightgramchangeinmousemodel.xlsx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 04 Feb, 2026 Reviews received at journal 03 Feb, 2026 Reviews received at journal 27 Jan, 2026 Reviewers agreed at journal 20 Jan, 2026 Reviewers agreed at journal 12 Jan, 2026 Reviewers invited by journal 09 Jan, 2026 Editor assigned by journal 29 Dec, 2025 Editor invited by journal 19 Dec, 2025 Submission checks completed at journal 17 Dec, 2025 First submitted to journal 17 Dec, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8031602","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":573453920,"identity":"d8ed8bdd-410e-4b1d-9ab5-efa6f1e458ff","order_by":0,"name":"Sribalasubashini Muralimanoharan","email":"","orcid":"","institution":"UT Health San Antonio","correspondingAuthor":false,"prefix":"","firstName":"Sribalasubashini","middleName":"","lastName":"Muralimanoharan","suffix":""},{"id":573453921,"identity":"4fde34c2-546b-450b-89fd-0deacf4e9370","order_by":1,"name":"Ana Corachán","email":"","orcid":"","institution":"IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigacion Sanitaria La Fe","correspondingAuthor":false,"prefix":"","firstName":"Ana","middleName":"","lastName":"Corachán","suffix":""},{"id":573453924,"identity":"db113962-874e-4a9a-8233-145fcf1a293b","order_by":2,"name":"Azad Khosh","email":"","orcid":"","institution":"UT Health San Antonio","correspondingAuthor":false,"prefix":"","firstName":"Azad","middleName":"","lastName":"Khosh","suffix":""},{"id":573453925,"identity":"72104452-f4a9-4308-b33d-a624f3d0d19a","order_by":3,"name":"Sierra Hathaway","email":"","orcid":"","institution":"UT Health San Antonio","correspondingAuthor":false,"prefix":"","firstName":"Sierra","middleName":"","lastName":"Hathaway","suffix":""},{"id":573453926,"identity":"a88b5539-9848-4c38-8117-bc8839ea668f","order_by":4,"name":"Susivarshini Karthigayan","email":"","orcid":"","institution":"UT Health San Antonio","correspondingAuthor":false,"prefix":"","firstName":"Susivarshini","middleName":"","lastName":"Karthigayan","suffix":""},{"id":573453930,"identity":"261b4731-55fc-4ac5-993e-c99a03816f15","order_by":5,"name":"Claire Schenken","email":"","orcid":"","institution":"UT Health San Antonio","correspondingAuthor":false,"prefix":"","firstName":"Claire","middleName":"","lastName":"Schenken","suffix":""},{"id":573453933,"identity":"ebd409c9-a26c-488f-bc2d-deacdad4a3a2","order_by":6,"name":"Nicholas Stansbury","email":"","orcid":"","institution":"UT Health San Antonio","correspondingAuthor":false,"prefix":"","firstName":"Nicholas","middleName":"","lastName":"Stansbury","suffix":""},{"id":573453934,"identity":"ae479617-4361-4c89-8827-b9b96d37e461","order_by":7,"name":"Robert Schenken","email":"","orcid":"","institution":"UT Health San Antonio","correspondingAuthor":false,"prefix":"","firstName":"Robert","middleName":"","lastName":"Schenken","suffix":""},{"id":573453935,"identity":"e888bf56-fb0f-4e39-accf-4ea6403ebe87","order_by":8,"name":"Maria Victoria Bariani","email":"","orcid":"","institution":"University of Chicago","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Victoria","lastName":"Bariani","suffix":""},{"id":573453939,"identity":"f8e53f7e-3303-436e-991a-f3fa18fb3445","order_by":9,"name":"Qiwei Yang","email":"","orcid":"","institution":"University of Chicago","correspondingAuthor":false,"prefix":"","firstName":"Qiwei","middleName":"","lastName":"Yang","suffix":""},{"id":573453940,"identity":"7a327a9f-c81a-4e94-a8f3-944d2cedfe3b","order_by":10,"name":"Eloise Dray","email":"","orcid":"","institution":"UT Health San Antonio","correspondingAuthor":false,"prefix":"","firstName":"Eloise","middleName":"","lastName":"Dray","suffix":""},{"id":573453941,"identity":"5d7ff53d-4d1e-488e-a5b5-c18071ae2189","order_by":11,"name":"Mazhar Adli","email":"","orcid":"","institution":"Northwestern University","correspondingAuthor":false,"prefix":"","firstName":"Mazhar","middleName":"","lastName":"Adli","suffix":""},{"id":573453942,"identity":"07c4c91e-f83b-4e0c-8e76-93d546fe6e6f","order_by":12,"name":"Hortensia Ferrero","email":"","orcid":"","institution":"IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigacion Sanitaria La Fe","correspondingAuthor":false,"prefix":"","firstName":"Hortensia","middleName":"","lastName":"Ferrero","suffix":""},{"id":573453943,"identity":"5fc2ec7d-5b36-4aa2-a3d1-0eb94db0285d","order_by":13,"name":"Ayman Al-Hendy","email":"","orcid":"","institution":"University of Chicago","correspondingAuthor":false,"prefix":"","firstName":"Ayman","middleName":"","lastName":"Al-Hendy","suffix":""},{"id":573453944,"identity":"24965b77-8579-4769-af9b-61669f4d537d","order_by":14,"name":"Thomas G. 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fibroids","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8031602/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8031602/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Uterine fibroids (UFs) are the most important benign neoplastic threat to women’s health worldwide, with no long-term noninvasive treatment options currently available. Among known UF driver alterations, somatic mutations in Mediator subunit MED12 are by the far the most prevalent, accounting for up to 80% of these clinically significant lesions. Although it is presently unclear how MED12 mutations trigger neoplastic transformation, MED12-mutant UFs are nonetheless characterized by significant chromosomal loss and rearrangement, suggesting genomic instability as a driving force in tumor development. However, the basis by which MED12 mutations drive genomic instability is not known. Herein, we show that R-loop-driven replication stress in MED12-mutant UFs leads to DNA under-replication and mitotic segregation errors that drive chromosomal instability. Notably, we find that vitamin D3 (VD3), a modifiable risk factor in UF development, suppresses pathogenic R-loop accrual and ameliorates replication stress-driven chromosomal instability, contributing to growth inhibition of patient-derived MED12-mutant UF xenografts in vivo. Altogether these findings uncover a molecular basis by which the predominant UF driver converges with a known risk factor at the interface of genomic instability, with significant translational implications for personalized UF prevention and treatment.","manuscriptTitle":"Vitamin D3 ameliorates R-loop-induced replication stress and chromosomal instability in MED12-mutant uterine fibroids","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-13 14:40:48","doi":"10.21203/rs.3.rs-8031602/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-05T04:49:52+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-03T19:48:57+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-27T22:02:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"42915165517000472375952456484277129255","date":"2026-01-20T19:48:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"182072366405682608793114555644972933525","date":"2026-01-12T17:50:15+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-09T14:07:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-30T02:13:24+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-19T11:46:06+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-17T17:36:06+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-12-17T17:28:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2f6c96cf-0f62-46c4-a494-cb4153ef757e","owner":[],"postedDate":"January 13th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":61017212,"name":"Biological sciences/Cancer"},{"id":61017214,"name":"Health sciences/Diseases"},{"id":61017216,"name":"Biological sciences/Genetics"},{"id":61017218,"name":"Biological sciences/Molecular biology"},{"id":61017219,"name":"Health sciences/Molecular medicine"},{"id":61017220,"name":"Health sciences/Oncology"}],"tags":[],"updatedAt":"2026-04-11T02:38:18+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-13 14:40:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8031602","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8031602","identity":"rs-8031602","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}