FMRP as a Key Regulator of Stress Granule Dynamics in Cholangiocarcinoma and Melanoma Cells

FMRP as a Key Regulator of Stress Granule Dynamics in Cholangiocarcinoma and Melanoma Cells | 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 FMRP as a Key Regulator of Stress Granule Dynamics in Cholangiocarcinoma and Melanoma Cells Elena Santonico, Federica Ferrentino, Silvia Cavaliere, Giulia Leanza, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7428401/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 11 You are reading this latest preprint version Abstract Stress granules (SGs) are dynamic, phase-dense cytosolic particles whose properties are dominated by weak interactions between proteins and RNAs. They form in response to cellular stress and play a critical role in regulating mRNA metabolism and cell survival. The Fragile X Messenger Ribonucleoprotein 1 (FMRP), a multifunctional RNA-binding protein mutated or absent in Fragile X Syndrome, has recently emerged as a key player in SG biology and cancer progression. In this study, we investigate the role of FMRP in SG assembly in liver and melanoma cancer cells exposed to oxidative stress induced by sodium arsenite. We demonstrate that FMRP co-localizes with the SG marker G3BP1 and is essential for its stability and cytoplasmic localization. Depletion of FMRP leads to a significant reduction in G3BP1 expression, impaired SG formation, and increased cellular sensitivity to stress. Furthermore, FMRP interacts with other SG components, including TIA-1, and modulates the organization of SGs without affecting TIA-1 expression. Our findings highlight FMRP as a central regulator of SG dynamics and suggest that targeting the FMRP–G3BP1 axis may offer novel therapeutic opportunities in aggressive and treatment-resistant cancers. Biological sciences/Cell biology/Cellular imaging/Super-resolution microscopy Biological sciences/Cell biology/Mechanisms of disease Full Text Additional Declarations (Not answered) Supplementary Files SupplementalMaterial.pdf Supplemental material Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: revise 23 Sep, 2025 Review # 3 received at journal 22 Sep, 2025 Review # 2 received at journal 19 Sep, 2025 Reviewer # 3 agreed at journal 15 Sep, 2025 Review # 1 received at journal 14 Sep, 2025 Reviewer # 2 agreed at journal 04 Sep, 2025 Reviewer # 1 agreed at journal 03 Sep, 2025 Reviewers invited by journal 03 Sep, 2025 Submission checks completed at journal 22 Aug, 2025 Editor assigned by journal 21 Aug, 2025 First submitted to journal 21 Aug, 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-7428401","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":509495968,"identity":"471c786b-dde6-43b7-858f-c7b3a0f92424","order_by":0,"name":"Elena Santonico","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-3897-8990","institution":"Campus Bio Medico University of Rome","correspondingAuthor":true,"prefix":"","firstName":"Elena","middleName":"","lastName":"Santonico","suffix":""},{"id":509495969,"identity":"d807d1d5-3165-45e8-981a-744f105f4ad1","order_by":1,"name":"Federica Ferrentino","email":"","orcid":"","institution":"School of Basic and Medical Biosciences, King’s College","correspondingAuthor":false,"prefix":"","firstName":"Federica","middleName":"","lastName":"Ferrentino","suffix":""},{"id":509495970,"identity":"ca051d0e-aeda-4ff1-96ed-5d485cc92807","order_by":2,"name":"Silvia Cavaliere","email":"","orcid":"","institution":"Campus Bio-Medico University","correspondingAuthor":false,"prefix":"","firstName":"Silvia","middleName":"","lastName":"Cavaliere","suffix":""},{"id":509495971,"identity":"0704ec2b-d54f-4167-befa-15fdca5d8a25","order_by":3,"name":"Giulia Leanza","email":"","orcid":"","institution":"Campus Bio-Medico University","correspondingAuthor":false,"prefix":"","firstName":"Giulia","middleName":"","lastName":"Leanza","suffix":""},{"id":509495972,"identity":"26734b6b-fe3f-4d03-a0b5-b715e33c65ea","order_by":4,"name":"Francesco Pantano","email":"","orcid":"","institution":"Campus Bio-Medico University","correspondingAuthor":false,"prefix":"","firstName":"Francesco","middleName":"","lastName":"Pantano","suffix":""},{"id":509495973,"identity":"e86f29d5-80cd-429b-bc69-805d67108858","order_by":5,"name":"Nicola Napoli","email":"","orcid":"","institution":"Campus Bio-Medico University","correspondingAuthor":false,"prefix":"","firstName":"Nicola","middleName":"","lastName":"Napoli","suffix":""},{"id":509495974,"identity":"2730294c-63e4-4042-b75b-76be1f60f56f","order_by":6,"name":"Francesca Zalfa","email":"","orcid":"https://orcid.org/0000-0002-1922-9468","institution":"Campus Bio-Medico University of Rome","correspondingAuthor":false,"prefix":"","firstName":"Francesca","middleName":"","lastName":"Zalfa","suffix":""},{"id":509495975,"identity":"5c7b3faf-2f54-4483-a994-5190588354cf","order_by":7,"name":"Simone Carotti","email":"","orcid":"https://orcid.org/0000-0002-3164-1500","institution":"University Campus Bio-Medico","correspondingAuthor":false,"prefix":"","firstName":"Simone","middleName":"","lastName":"Carotti","suffix":""}],"badges":[],"createdAt":"2025-08-21 17:26:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7428401/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7428401/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90928813,"identity":"3f76d05e-5ae4-483a-94a9-b0fb528a8bb9","added_by":"auto","created_at":"2025-09-09 16:01:08","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5217302,"visible":true,"origin":"","legend":"","description":"","filename":"SantonicoEetal2025.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7428401/v1_covered_2fdb4961-a3c0-47f9-a539-1e3d7d797c1d.pdf"},{"id":90927338,"identity":"5bc6c7c7-a89c-4fce-bd17-4674ddf22ce4","added_by":"auto","created_at":"2025-09-09 15:45:06","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1295541,"visible":true,"origin":"","legend":"Supplemental material","description":"","filename":"SupplementalMaterial.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7428401/v1/49939a90d88700de3f268454.pdf"}],"financialInterests":"(Not answered)","formattedTitle":"\u003cp\u003eFMRP as a Key Regulator of Stress Granule Dynamics in Cholangiocarcinoma and Melanoma Cells\u003c/p\u003e","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":"cell-death-and-disease","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"cddis","sideBox":"Learn more about [Cell Death \u0026 Disease](http://www.nature.com/cddis/)","snPcode":"41419","submissionUrl":"https://mts-cddis.nature.com/cgi-bin/main.plex","title":"Cell Death \u0026 Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7428401/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7428401/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Stress granules (SGs) are dynamic, phase-dense cytosolic particles whose properties are dominated by weak interactions between proteins and RNAs. They form in response to cellular stress and play a critical role in regulating mRNA metabolism and cell survival. The Fragile X Messenger Ribonucleoprotein 1 (FMRP), a multifunctional RNA-binding protein mutated or absent in Fragile X Syndrome, has recently emerged as a key player in SG biology and cancer progression. In this study, we investigate the role of FMRP in SG assembly in liver and melanoma cancer cells exposed to oxidative stress induced by sodium arsenite. We demonstrate that FMRP co-localizes with the SG marker G3BP1 and is essential for its stability and cytoplasmic localization. Depletion of FMRP leads to a significant reduction in G3BP1 expression, impaired SG formation, and increased cellular sensitivity to stress. Furthermore, FMRP interacts with other SG components, including TIA-1, and modulates the organization of SGs without affecting TIA-1 expression. Our findings highlight FMRP as a central regulator of SG dynamics and suggest that targeting the FMRP–G3BP1 axis may offer novel therapeutic opportunities in aggressive and treatment-resistant cancers.","manuscriptTitle":"FMRP as a Key Regulator of Stress Granule Dynamics in Cholangiocarcinoma and Melanoma Cells","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-09 15:45:01","doi":"10.21203/rs.3.rs-7428401/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2025-09-23T13:47:27+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-09-23T03:53:29+00:00","index":3,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-09-19T13:35:44+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-09-15T08:00:39+00:00","index":3,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-09-14T12:12:24+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-09-04T10:52:33+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-09-03T08:50:32+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2025-09-03T07:14:35+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-22T10:25:57+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-21T17:23:31+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cell Death \u0026 Disease","date":"2025-08-21T17:23:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cell-death-and-disease","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"cddis","sideBox":"Learn more about [Cell Death \u0026 Disease](http://www.nature.com/cddis/)","snPcode":"41419","submissionUrl":"https://mts-cddis.nature.com/cgi-bin/main.plex","title":"Cell Death \u0026 Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3f28ab86-10c8-40bb-95c0-0eecfefadf3b","owner":[],"postedDate":"September 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[{"id":54453676,"name":"Biological sciences/Cell biology/Cellular imaging/Super-resolution microscopy"},{"id":54453677,"name":"Biological sciences/Cell biology/Mechanisms of disease"}],"tags":[],"updatedAt":"2026-04-15T13:05:17+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-09 15:45:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7428401","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7428401","identity":"rs-7428401","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}