Assessing the contribution of rare DNA states to cancer mutational signatures using sequence-specific conformational fingerprinting

Assessing the contribution of rare DNA states to cancer mutational signatures using sequence-specific conformational fingerprinting | 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 Assessing the contribution of rare DNA states to cancer mutational signatures using sequence-specific conformational fingerprinting Hashim Al-Hashimi, Or Szekely, Yeongjoon Lee, Atul Rangadurai, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8012102/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 Rare and short-lived DNA conformations are proposed to be key drivers of mutagenesis, yet assessing their contribution to mutational signatures found in human cancers remains challenging. Here, we developed an approach that quantifies the sequence-dependent propensity to form a rare DNA conformation and compares the resulting fingerprint against cancer mutational signatures. Using 19 F NMR, we measured the propensity for the anionic Watson-Crick-like G•T − conformation across all sixteen triplet sequence contexts and discovered a striking 50-fold variation driven by suboptimal interactions between anionic thymine and its 3' neighbor. Comparing this fingerprint, and those of other rare DNA states, against the COSMIC database uncovered plausible links to mutational processes associated with exposure to damaging agents and therapies. Thus, integrating molecular biophysics with genomic epidemiology provides a powerful framework to explore how DNA’s dynamic properties shape genome stability and influence human disease. Biological sciences/Biochemistry/DNA Biological sciences/Cancer Biological sciences/Structural biology/NMR spectroscopy/Solution-state NMR DNA dynamics DNA damage deprotonation anion mismatches Hoogsteen 19F NMR pKa Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SzekelyExcitedCancerStatesSI.pdf Supplemental Material 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. 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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-8012102","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":544545961,"identity":"5d419abf-50dc-4369-8935-9b55a0b1dfee","order_by":0,"name":"Hashim 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