Network Architecture Determines Delay Robustness in the Spindle Assembly Checkpoint

Network Architecture Determines Delay Robustness in the Spindle Assembly Checkpoint | 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 Network Architecture Determines Delay Robustness in the Spindle Assembly Checkpoint Bashar Ibrahim This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9337396/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 12 You are reading this latest preprint version Abstract The spindle assembly checkpoint (SAC) ensures accurate chromosome segregation during mitosis by preventing premature activation of the anaphase-promoting complex/cyclosome (APC/C). Despite its critical role in maintaining genomic stability, most mathematical models of the SAC treat underlying biochemical processes as instantaneous, neglecting experimentally observed delays arising from molecular activation, complex assembly, and intracellular transport. How such temporal structure interacts with network architecture to shape checkpoint dynamics remains unclear.%Here, we develop a distributed-delay framework and incorporate experimentally motivated delays into multiple mechanistic SAC architectures. Using a gamma-chain formulation, we perform systematic stability and bifurcation analyses across representative models. We find that biologically realistic delays fundamentally reorganize system dynamics, partitioning SAC architectures into two distinct classes: delay-robust designs that preserve strong APC/C inhibition, and delay-sensitive designs in which checkpoint control collapses.%Motivated by this classification, we introduce a bistable template architecture that combines mechanistic Mad2 templating with an autocatalytic feedback loop. This design maintains bistability and high inhibition across a broad range of physiological delays and remains resilient under stochastic perturbations.%These results identify network architecture as a key determinant of robustness to molecular timing and demonstrate that distributed delays can stabilize, rather than destabilize, checkpoint function by enabling temporal integration and memory-like behavior. More broadly, this work establishes delay-aware design principles for biochemical decision-making systems in which intermediate processes are intrinsically time-distributed. Biological sciences/Biophysics Biological sciences/Computational biology and bioinformatics Physical sciences/Mathematics and computing Physical sciences/Physics Biological sciences/Systems biology Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 14 May, 2026 Reviews received at journal 14 May, 2026 Reviews received at journal 14 May, 2026 Reviewers agreed at journal 08 May, 2026 Reviewers agreed at journal 06 May, 2026 Reviewers agreed at journal 06 May, 2026 Reviewers agreed at journal 06 May, 2026 Reviewers invited by journal 06 May, 2026 Editor invited by journal 09 Apr, 2026 Editor assigned by journal 08 Apr, 2026 Submission checks completed at journal 08 Apr, 2026 First submitted to journal 06 Apr, 2026 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-9337396","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":638089047,"identity":"52934893-2a7a-4e9d-b58f-dc0dc9006057","order_by":0,"name":"Bashar Ibrahim","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6UlEQVRIie3RMQrCMBSA4SeBdgmdEyJ6hUgHKXqYSKFTBydXC4KT7kov4eQsCHZxFksXO3kAl4oOvlZdQ0bB/FtCPvJIAGy2H8xhAAQkgHSTz9YON8wI3eFSGRBoCCaZMiSeWJa38XgLfX498XsFHe+siE91g7UzX6xkAUEaTwRV4HMkoZawCARFIos4EjjYaINkH+sJeTQkP0a8UjA1Ic77lrN7YDiYkvVgWtI+OAMkNFjEZEAj1lsfy5n/1JBuOicFfRadvpuVeTUcdr0s3POVhnzDJ6L4ofU3QSsxAE3uxfSkzWaz/VkvSf9EcatLq7kAAAAASUVORK5CYII=","orcid":"","institution":"Gulf University for Science \u0026 Technology","correspondingAuthor":true,"prefix":"","firstName":"Bashar","middleName":"","lastName":"Ibrahim","suffix":""}],"badges":[],"createdAt":"2026-04-06 21:53:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9337396/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9337396/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":109296111,"identity":"8b05ff3e-bb30-4661-8d2d-a17f4cba6a81","added_by":"auto","created_at":"2026-05-15 08:45:46","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":599917,"visible":true,"origin":"","legend":"","description":"","filename":"LocalizationDelaySciReports2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9337396/v1_covered_ee8e700d-7525-4fee-8db0-35fa20cd9113.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Network Architecture Determines Delay Robustness in the Spindle Assembly Checkpoint","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-9337396/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9337396/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"The spindle assembly checkpoint (SAC) ensures accurate chromosome segregation during mitosis by preventing premature activation of the anaphase-promoting complex/cyclosome (APC/C). Despite its critical role in maintaining genomic stability, most mathematical models of the SAC treat underlying biochemical processes as instantaneous, neglecting experimentally observed delays arising from molecular activation, complex assembly, and intracellular transport. How such temporal structure interacts with network architecture to shape checkpoint dynamics remains unclear.%Here, we develop a distributed-delay framework and incorporate experimentally motivated delays into multiple mechanistic SAC architectures. Using a gamma-chain formulation, we perform systematic stability and bifurcation analyses across representative models. 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