Induced DNA double strand breaks by anti-cancer drugs occur at active transcription histone mark H3K36 tri-methylation

Induced DNA double strand breaks by anti-cancer drugs occur at active transcription histone mark H3K36 tri-methylation | 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 Induced DNA double strand breaks by anti-cancer drugs occur at active transcription histone mark H3K36 tri-methylation Wenyi Feng, ishita Joshi, Dattatray Sawant, Jeffrey Ng This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8168296/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Many anti-cancer clastogens are known to induce DNA replication stress and ultimately DNA double-strand breaks (DSBs), one of the most deleterious forms of DNA damage and threat to genome integrity. However, the mechanism(s) by which these replication inhibitors cause DSB is unclear. Our previous work suggested that replication inhibitors induce DSB at transcriptionally up-regulated genes, particularly those oriented in a head-on configuration with respect to incoming replication. Here, we rigorously test this model by simultaneously mapping the transcriptome and genome-wide DSBs induced by six replication inhibitors with diverse mechanisms of action (hy-droxyurea, methyl-methane sulfonate, camptothecin, actinomycin, doxorubicin and methotrexate). Our data show that replication inhibitor-induced DSBs are enriched in genic regions and show a positive correlation with active transcription histone marks, particularly histone H3 lysine 36 tri-methylation. We further demonstrated that camptothecin-induced DSBs were significantly reduced by deletion of Set2, the known H3K36 methyltransferase, and to a lesser extent, by deletion of Rpd3, a histone deacetylase recognizing H3K36 trimethylation. Our data provide support for a model where DSBs are driven by replication inhibitor-induced replication-transcription conflict. More importantly, they reveal active transcription histone markers as the impediments for replica-tion fork progression, therefore a direct culprit for DSBs. Biological sciences/Molecular biology/DNA damage and repair/Double-strand DNA breaks Biological sciences/Genetics/Genomic instability Biological sciences/Genetics/Gene expression Full Text Additional Declarations There is NO Competing Interest. Supplementary Files TableS1082825.xlsx Table S1 Cite Share Download PDF Status: Under Review 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-8168296","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":556541839,"identity":"af418124-940b-4a56-bcc0-4be92e08ba15","order_by":0,"name":"Wenyi 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