Histone Variant H2A.B.3 Orchestrates a New Nuclear Pathway for Histone mRNA Decay

Histone Variant H2A.B.3 Orchestrates a New Nuclear Pathway for Histone mRNA Decay | 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 Biological Sciences - Article Histone Variant H2A.B.3 Orchestrates a New Nuclear Pathway for Histone mRNA Decay Tatiana Soboleva, Mohd Nazmul Hasan Apu, Jun Hee Lim, Marianna Volpert, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8304477/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Replication-dependent (RD) histones are key proteins that ensure continuous DNA packaging during cell division. In dividing cells, RD histone mRNAs are produced during S phase and rapidly degraded afterwards in an UPF1-dependent manner. However, RD histone mRNA regulation in non-dividing cells has remained largely unclear. This study uncovers a new nuclear pathway controlling RD histone mRNA degradation in non-dividing, post-meiotic male spermatids. The process depends on the histone variant H2A.B.3, which is enriched at nucleosomes within histone gene clusters and interacts with UPF1 in an RNA-dependent manner. Loss of H2A.B.3 leads to abnormal stabilisation of histone mRNAs in haploid germ cells, revealing a unique post-meiotic mechanism for histone mRNA turnover. We demonstrate that H2A.B.3 binds the stem-loop structure of RD histone mRNA. This interaction facilitates the recruitment of active phosphorylated UPF1 (phUPF1) to RD histone mRNA in the nucleus, promoting its degradation by the nuclear exosome. Overexpression of H2A.B.3 enhances RD histone mRNA decay, while UPF1 depletion abolishes this effect. Collectively, these findings define a mechanism by which H2A.B.3 recognises the histone mRNA stem-loop and recruits UPF1, revealing a previously unrecognised nuclear function of UPF1 that links histone variant–mediated chromatin regulation to selective histone mRNA degradation required for histone–protamine exchange and male fertility. These findings uncover an alternative nuclear mechanism of histone mRNA degradation crucial for histone-protamine exchange and male fertility and may also have broader implications for malignancies in which H2A.B is upregulated. Biological sciences/Molecular biology/RNA metabolism/RNA decay Biological sciences/Genetics/Gene expression Biological sciences/Developmental biology/Germline development/Spermatogenesis Full Text Additional Declarations There is NO Competing Interest. Supplementary Files ExtendedDataTable2.xlsx Data table 2 ExtendedMethodsTable1.xlsx Methods table ExtendedDataTable1.xlsx Data table 1 Cite Share Download PDF Status: Posted Version 1 posted 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-8304477","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":556865440,"identity":"0826f3cc-0f11-45b4-a1f3-074c7997eb3c","order_by":0,"name":"Tatiana 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