KRCC1, a novel modulator of the DNA damage response

KRCC1, a novel modulator of the DNA damage response | 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 KRCC1, a novel modulator of the DNA damage response Fiifi Neizer-Ashun, Shailendra Dwivedi, Anindya Dey, Elangovan Thavathiru, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1514922/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 The lysine rich coiled-coil 1 (KRCC1) protein is overexpressed in multiple malignancies including ovarian cancer and overexpression correlates with poor overall survival. Despite a potential role in cancer progression, the biology of KRCC1 remains elusive. Here we characterize the biology of KRCC1 and define its role in the DNA damage response and in cell cycle progression. We demonstrate that KRCC1 associates with the checkpoint kinase 1 (CHK1) upon DNA damage and regulates the CHK1-mediated checkpoint. KRCC1 facilitates RAD51 recombinase (RAD51) foci formation and augments homologous recombination repair. Furthermore, KRCC1 is required for proper S-phase progression and subsequent mitotic entry. Our findings uncover a novel component of the DNA damage response and a potential link between cell cycle, associated damage response, and DNA repair. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryFigure1.tif Supplemental Figure S1 KRCC1 regulates the CHK1-mediated checkpoint.A. OV90 cells treated with or without CPT and ATR inhibitor (ATRi) were immunoblotted for pCHK1-S345 and pCHK1-S296.B. Stable OV90 cell lines expressing sh-RNA targeting KRCC1 (shKRCC1) or non-target shRNA (shCTL) were immunoblotted for markers of CHK1-mediated DDR.C. OV90 cells were transfected with 0.5µg, 0.75µg, or 1.5µg of HAKRCC1 following control or KRCC1 depletion by siRNA.D. OV90 cells were transfected with control siRNA (siCTL) and treated with or without CPT (1µM for 1hr) or transfected with WT-CHK1, CA-CHK1, or 1.5µg of HAKRCC1 following KRCC1 depletion by siRNA. Overexpressed (Exo) and endogenous (Endo) proteins shown; indicates KRCC1. SupplementaryFigure2.tif Supplemental Figure S2 Silencing KRCC1 inhibits RAD51 foci formation resulting in unrepaired DNA damage.A. Immunofluorescence images of OV90 cells transfected with control or KRCC1 siRNA and treated with CPT (1µM for 1hr) were released for 8hrs and collected at 2hr intervals.B. Quantitation of γH2AX from immunofluorescence of OV90 cells transfected with control or KRCC1 siRNA and treated with CPT (1µM for 1hr) were released for 24hrs and collected at indicated timepoints. Cells with >10 foci were scored as positive. SupplementaryFigure3.tif Supplemental Figure S3 KRCC1 promotes optimal S-phase progression.A, B. Relative EdU intensities of HeLa, U2OS, and OV90 cells transfected with control or KRCC1 siRNA and labeled with EdU for 15min and assessed by flow cytometry.C. Percentage of OV90 cells at the late S-G2 boundary in control and KRCC1 siRNA transfected conditions.D. Aysnchronous HeLa cells transfected with control or KRCC1 siRNA or with HAKRCC1 following KRCC1 depletion were labeled with EdU for 15min and assessed by flow cytometry for cell cycle distribution. 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-1514922","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":96466869,"identity":"52934862-4f09-4341-822e-bf576cc5317e","order_by":0,"name":"Fiifi Neizer-Ashun","email":"","orcid":"","institution":"The University of Oklahoma Health Sciences Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Fiifi","middleName":"","lastName":"Neizer-Ashun","suffix":""},{"id":96466870,"identity":"a8c8bd0f-7e56-4756-a92e-290964cf15b1","order_by":1,"name":"Shailendra Dwivedi","email":"","orcid":"","institution":"OUHSC","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shailendra","middleName":"","lastName":"Dwivedi","suffix":""},{"id":96466871,"identity":"a1b4e5f5-b0a6-4358-b88f-5028fa5e8035","order_by":2,"name":"Anindya Dey","email":"","orcid":"","institution":"The University of Oklahoma Health Sciences Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Anindya","middleName":"","lastName":"Dey","suffix":""},{"id":96466872,"identity":"dc957bf0-9da6-4501-b37d-519493359c60","order_by":3,"name":"Elangovan Thavathiru","email":"","orcid":"","institution":"The University of Oklahoma Health Sciences Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Elangovan","middleName":"","lastName":"Thavathiru","suffix":""},{"id":96466873,"identity":"281413f1-77b7-4ea2-ac3b-c7190abbbef0","order_by":4,"name":"William Berry","email":"","orcid":"","institution":"The University of Oklahoma Health Sciences Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"William","middleName":"","lastName":"Berry","suffix":""},{"id":96466874,"identity":"fe667dc7-0112-4f96-bf91-7a253dcea201","order_by":5,"name":"Susan Lees-Miller","email":"","orcid":"https://orcid.org/0000-0001-5809-2516","institution":"University of Calgary","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Susan","middleName":"","lastName":"Lees-Miller","suffix":""},{"id":96466875,"identity":"cb4025ed-d4fd-4c43-ae91-2a9f8b4e2d89","order_by":6,"name":"Priyabrata Mukherjee","email":"","orcid":"","institution":"University of Oklahoma Health Sciences Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Priyabrata","middleName":"","lastName":"Mukherjee","suffix":""},{"id":96466876,"identity":"ddbc247b-2e2e-4fca-9f69-d818cfb4b416","order_by":7,"name":"Resham Bhattacharya","email":"data:image/png;base64,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","orcid":"","institution":"The University of Oklahoma Health Sciences Center","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Resham","middleName":"","lastName":"Bhattacharya","suffix":""}],"badges":[],"createdAt":"2022-04-01 21:07:59","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1514922/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1514922/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":20120529,"identity":"59fa6b5e-425c-499e-a355-c3fe0a71a7fc","added_by":"auto","created_at":"2022-04-08 14:33:40","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":990841,"visible":true,"origin":"","legend":"\u003cp\u003eKRCC1 promotes CHK1 activation and efficient checkpoint.\u003c/p\u003e\u003cp\u003eA, B. OV90 and U2OS cells were transfected with control siRNA (siCTL) or siRNA targeting KRCC1 (siKRCC1) for 72hrs. Cells were stained with DAPI and anti-RPA2 antibody and visualized by fluorescence microscopy (scale bar, 20 μm). Percentage of cells with \u0026gt;10 foci are quantitated. The data are from manual scoring of ~200 cells per condition and from 3 experiments ± SDs.\u003c/p\u003e\u003cp\u003eC. Lysates from above transfected siCTL and siKRCC1 OV90 and U2OS cells were analyzed by immunoblotting for CHK1-mediated DDR markers.\u003c/p\u003e\u003cp\u003eD. Immunoblotting for markers of CHK1 mediated DDR markers after 72hrs KRCC1 silencing in the presence or absence of camptothecin (CPT, 1μM for 1hr).\u003c/p\u003e\u003cp\u003eE. KRCC1 interaction with CHK1 and 14-3-3 was evaluated using co-immunoprecipitation in empty vector (EV) or HA-tagged KRCC1 (HA-KRCC1) overexpressed cells treated with or without CPT (3μM, 2hrs).\u003c/p\u003e\u003cp\u003eF. CHK1 interaction with KRCC1 was evaluated using co-immunoprecipitation in empty vector (EV) or Halo-tagged KRCC1 (Halo-KRCC1) overexpressed cells treated with CPT in the presence or absence of ATRi (2μM, 16hrs). Marker (M) and IgG lanes are shown.\u003c/p\u003e\u003cp\u003eG. Proposed Model of CHK1 activation. After ATR-dependent phosphorylation of CHK1, CHK1 associates with KRCC1 and 14-3-3 to facilitate autophosphorylation at S296 to activate the kinase.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1514922/v1/7fbc32565826f9a549a6fc7e.jpg"},{"id":20120530,"identity":"064587c9-971f-408e-b33f-83e92d3fc8d7","added_by":"auto","created_at":"2022-04-08 14:33:40","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":881428,"visible":true,"origin":"","legend":"\u003cp\u003eKRCC1 inhibition suppresses homologous recombination repair.\u003c/p\u003e\u003cp\u003eA. Schematic of functional HRR assay\u003c/p\u003e\u003cp\u003eB. Live cell images of DR-GFP U2OS cells were transfected with I-SceI endonuclease in the presence or absence of KRCC1 siRNA.\u003c/p\u003e\u003cp\u003eC. Quantitation of GFP positive cells from live imaging. The data are from manual scoring of ~300 cells per condition and from 3 experiments ± SDs.\u003c/p\u003e\u003cp\u003eD, E. OV90 and U2OS cells transfected with control siRNA (siCTL) or siRNA targeting KRCC1 (siKRCC1) were treated with CPT (1μM for 1hr) and released for 2hrs. Cells were stained with DAPI and anti-RAD51 antibody and visualized by fluorescence microscopy. Percentage of cells with \u0026gt;10 foci are quantitated. The data are from manual scoring of ~200 cells per condition and from 3 experiments ± SDs.\u003c/p\u003e\u003cp\u003eF. Experimental design of G, H. OV90 cells transfected with control or KRCC1 siRNA and treated with CPT (1μM for 1hr) were released for 8hrs and collected at 2hr intervals. Quantitation of γH2AX and RAD51. Cells with \u0026gt;10 foci were scored as positive. The data are from manual scoring of ~200 cells per condition and from 3 experiments ± SDs.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1514922/v1/2bcce97f9eab841eaad0377d.jpg"},{"id":20121346,"identity":"57af2ba8-58cc-4ae4-88f2-69194c0aa7db","added_by":"auto","created_at":"2022-04-08 14:43:40","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1373818,"visible":true,"origin":"","legend":"\u003cp\u003eSilencing KRCC1 results in delayed S-phase progression and accumulation of cells at the late S phase.\u003c/p\u003e\u003cp\u003eAsynchronous HeLa and U2OS cells transfected with control or KRCC1 siRNA and labeled with 20µM EdU for 15min. DNA synthesis, DNA content, and cell cycle distribution were assessed by flow cytometry.\u003c/p\u003e\u003cp\u003eA. Experimental images of the EdU/PI distribution of control and KRCC1 silenced cells.\u003c/p\u003e\u003cp\u003eB. Percentage of cells at the late S-G2 boundary was calculated as a fraction of % EdU+ cells in the small gate over % total EdU+ cells.\u003c/p\u003e\u003cp\u003eC. HeLa cells transfected with control or KRCC1 siRNA or treated with CHK1 inhibitor (CHK1i, AZD7762) or CDC7 inhibitor (TAK-931) were labeled with EdU and subjected to flow cytometry.\u003c/p\u003e\u003cp\u003eD. HeLa cells were transfected with control or KRCC1 siRNA or or treated with CDC7 inhibitor (TAK-931) were G1-S synchronized by double thymidine block and released for 12hrs. The cells were collected at the indicated time points and analyzed by flow cytometry.\u003c/p\u003e\u003cp\u003eE. Immunoblotting of indicated proteins in control, KRCC1 depleted. CHK1 inhibited, or CDC7 inhibited cells. Short exposure (SE) and long exposure (LE) blots for pMCM2-S40/41 are shown.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1514922/v1/bf0a91df56fa0caed07ae2ea.jpg"},{"id":20120532,"identity":"f850737b-e741-4cb1-81b2-1e381af83b89","added_by":"auto","created_at":"2022-04-08 14:33:40","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":720416,"visible":true,"origin":"","legend":"\u003cp\u003eKRCC1 depletion results in premature mitotic entry\u003c/p\u003e\u003cp\u003eA, B. HeLa and U2OS cells transfected with control or KRCC1 siRNA and labeled with 20µM EdU for 15 min. Cells were stained with DAPI following immunofluorescence was performed for EdU and pH3S10.\u003c/p\u003e\u003cp\u003eC. Percentage of pH3S10 positive cells.\u003c/p\u003e\u003cp\u003eD. Percentage of EdU and pH3S10 dual positive cells. The data shown are from 3 independent experiments ± SDs.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1514922/v1/24b754bab3a1ed7202470bee.jpg"},{"id":20121132,"identity":"e8dfcd56-32d8-4df1-95b4-87f55875dd37","added_by":"auto","created_at":"2022-04-08 14:38:40","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":574295,"visible":true,"origin":"","legend":"\u003cp\u003eModel of the role of KRCC1 in genome maintenance.\u003c/p\u003e\u003cp\u003eTo initiate replication, CDC7 phosphorylates MCM2 to induce origin firing. We speculate that when the replication fork encounters an obstacle, the KRCC1-CDC7 axis promotes MRE11-dependent degradation of reversed forks and subsequent restart. Depletion of KRCC1 may disrupt fork processing and restart resulting in replication stress. Replication stress and associated DNA damage should activate the CHK1-mediated checkpoint, however, absence of KRCC1 impairs CHK1 activation and CDC25A degradation. Additionally, inactive CHK1 may also compromise HRR. Overall, replication defects and failure to fully activate checkpoint may result in premature mitotic entry and subsequent apoptosis.\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1514922/v1/6218c4ea93e80840baf45e9d.jpg"},{"id":20121347,"identity":"46a3aaa6-9a93-45b3-8116-897087a1adbc","added_by":"auto","created_at":"2022-04-08 14:43:46","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":793446,"visible":true,"origin":"","legend":"","description":"","filename":"KRCC1PaperFinalNCB.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1514922/v1_covered.pdf"},{"id":20120534,"identity":"372c651d-cb16-4816-992b-7c612419962a","added_by":"auto","created_at":"2022-04-08 14:33:40","extension":"tif","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":3748912,"visible":true,"origin":"","legend":"\u003cp\u003eSupplemental Figure S1 KRCC1 regulates the CHK1-mediated checkpoint.\u003c/p\u003e\u003cp\u003eA. OV90 cells treated with or without CPT and ATR inhibitor (ATRi) were immunoblotted for pCHK1-S345 and pCHK1-S296.\u003c/p\u003e\u003cp\u003eB. Stable OV90 cell lines expressing sh-RNA targeting KRCC1 (shKRCC1) or non-target shRNA (shCTL) were immunoblotted for markers of CHK1-mediated DDR.\u003c/p\u003e\u003cp\u003eC. OV90 cells were transfected with 0.5µg, 0.75µg, or 1.5µg of HAKRCC1 following control or KRCC1 depletion by siRNA.\u003c/p\u003e\u003cp\u003eD. OV90 cells were transfected with control siRNA (siCTL) and treated with or without CPT (1µM for 1hr) or transfected with WT-CHK1, CA-CHK1, or 1.5µg of HAKRCC1 following KRCC1 depletion by siRNA. Overexpressed (Exo) and endogenous (Endo) proteins shown; indicates KRCC1.\u003c/p\u003e","description":"","filename":"SupplementaryFigure1.tif","url":"https://assets-eu.researchsquare.com/files/rs-1514922/v1/3b89f0b15cb9c353b9990334.tif"},{"id":20120535,"identity":"2b947280-6992-416e-b90a-106319a9fa8a","added_by":"auto","created_at":"2022-04-08 14:33:41","extension":"tif","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":6224464,"visible":true,"origin":"","legend":"\u003cp\u003eSupplemental Figure S2 Silencing KRCC1 inhibits RAD51 foci formation resulting in unrepaired DNA damage.\u003c/p\u003e\u003cp\u003eA. Immunofluorescence images of OV90 cells transfected with control or KRCC1 siRNA and treated with CPT (1µM for 1hr) were released for 8hrs and collected at 2hr intervals.\u003c/p\u003e\u003cp\u003eB. Quantitation of γH2AX from immunofluorescence of OV90 cells transfected with control or KRCC1 siRNA and treated with CPT (1µM for 1hr) were released for 24hrs and collected at indicated timepoints. Cells with \u0026gt;10 foci were scored as positive.\u003c/p\u003e","description":"","filename":"SupplementaryFigure2.tif","url":"https://assets-eu.researchsquare.com/files/rs-1514922/v1/71d39fa2c2969fd95f4880df.tif"},{"id":20120536,"identity":"bd143ecb-794d-4736-b25a-cd2a267e6091","added_by":"auto","created_at":"2022-04-08 14:33:41","extension":"tif","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":3624264,"visible":true,"origin":"","legend":"\u003cp\u003eSupplemental Figure S3 KRCC1 promotes optimal S-phase progression.\u003c/p\u003e\u003cp\u003eA, B. Relative EdU intensities of HeLa, U2OS, and OV90 cells transfected with control or KRCC1 siRNA and labeled with EdU for 15min and assessed by flow cytometry.\u003c/p\u003e\u003cp\u003eC. Percentage of OV90 cells at the late S-G2 boundary in control and KRCC1 siRNA transfected conditions.\u003c/p\u003e\u003cp\u003eD. Aysnchronous HeLa cells transfected with control or KRCC1 siRNA or with HAKRCC1 following KRCC1 depletion were labeled with EdU for 15min and assessed by flow cytometry for cell cycle distribution.\u003c/p\u003e","description":"","filename":"SupplementaryFigure3.tif","url":"https://assets-eu.researchsquare.com/files/rs-1514922/v1/9bb4144bb17dddd1565c33dd.tif"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"KRCC1, a novel modulator of the DNA damage response","fulltext":[{"header":"Full Text","content":"This preprint is available for \u003ca href='/article/rs-1514922/latest.pdf' target='_blank'\u003edownload as a PDF\u003c/a\u003e."}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-1514922/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1514922/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"The lysine rich coiled-coil 1 (KRCC1) protein is overexpressed in multiple malignancies including ovarian cancer and overexpression correlates with poor overall survival. Despite a potential role in cancer progression, the biology of KRCC1 remains elusive. Here we characterize the biology of KRCC1 and define its role in the DNA damage response and in cell cycle progression. We demonstrate that KRCC1 associates with the checkpoint kinase 1 (CHK1) upon DNA damage and regulates the CHK1-mediated checkpoint. KRCC1 facilitates RAD51 recombinase (RAD51) foci formation and augments homologous recombination repair. Furthermore, KRCC1 is required for proper S-phase progression and subsequent mitotic entry. Our findings uncover a novel component of the DNA damage response and a potential link between cell cycle, associated damage response, and DNA repair.","manuscriptTitle":"KRCC1, a novel modulator of the DNA damage response","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-04-08 14:33:38","doi":"10.21203/rs.3.rs-1514922/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6af94442-9be1-4cb7-b25c-1e18de8ede62","owner":[],"postedDate":"April 8th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-04-08T14:33:38+00:00","versionOfRecord":[],"versionCreatedAt":"2022-04-08 14:33:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1514922","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1514922","identity":"rs-1514922","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}