{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T20:28:36Z","timestamp":1772915316559,"version":"3.50.1"},"reference-count":16,"publisher":"World Scientific Pub Co Pte Ltd","issue":"01","funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["12371483"],"award-info":[{"award-number":["12371483"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Bioinform. Comput. Biol."],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:p>The dynamic p53 response is a known determinant of cell fate. However, its temporal control, specifically the mechanisms regulating the delay time ([Formula: see text]) of the graded p53 pulse following single-stranded breaks (SSBs), remains poorly understood. To systematically dissect this timing mechanism, we developed and analyzed a mechanistic ordinary differential equation (ODE) model of the p53-Mdm2-ATR network. We first established that increasing damage intensity reliably shortens the delay time, accelerating the cellular decision-making process. Our analysis revealed a critical finding: the delay time is most acutely sensitive to the p53-dependent Mdm2 production rate ([Formula: see text]), highlighting the dominant role of the negative feedback loop in setting the pace. We further classified the model parameters into functional roles: accelerators (e.g. Ataxia-Telangiectasia and RAD3-related (ATR) production rate dependent on damage ([Formula: see text]), p53 activation rate dependent on ATR ([Formula: see text]), p53-dependent Mdm2 production rate ([Formula: see text]), p53-dependent Wip1 production rate ([Formula: see text], ATR degradation rate ([Formula: see text]) and Mdm2-dependent p53 degradation rate ([Formula: see text], which shorten the delay time ([Formula: see text]), and brakes (e.g. ATR-dependent Mdm2 degradation rate ([Formula: see text]), self-degradation rate of Mdm2 ([Formula: see text]) and self-degradation rate of Wip1 ([Formula: see text]), which prolong it. Sensitivity analysis showed that as parameter values increase, [Formula: see text] becomes less sensitive to [Formula: see text]. The sensitivity to [Formula: see text] exhibited an initial increase followed by a decrease, whereas the opposite trend was observed for [Formula: see text]. The remaining parameters ([Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text]) all showed a monotonic decrease in sensitivity. This work provides a quantitative blueprint for therapeutic interventions, suggesting that targeting the p53-Mdm2 feedback strength is the most effective strategy to sensitize cancer cells and shorten the critical delay to cell death.<\/jats:p>","DOI":"10.1142\/s0219720026510017","type":"journal-article","created":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T04:10:08Z","timestamp":1769227808000},"source":"Crossref","is-referenced-by-count":0,"title":["Analysis of the regulation of model parameters on delay time in the p53 dynamical response to single-stranded breaks"],"prefix":"10.1142","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8125-9895","authenticated-orcid":false,"given":"Aiqing","family":"Ma","sequence":"first","affiliation":[{"name":"School of Financial Mathematics and Statistics, Guangdong University of Finance, Guangzhou 510521, P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4905-1162","authenticated-orcid":false,"given":"Xiyan","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Financial Mathematics and Statistics, Guangdong University of Finance, Guangzhou 510521, P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"219","published-online":{"date-parts":[[2026,2,17]]},"reference":[{"key":"S0219720026510017BIB001","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01347-1"},{"key":"S0219720026510017BIB002","doi-asserted-by":"publisher","DOI":"10.1126\/science.1905840"},{"key":"S0219720026510017BIB003","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2147"},{"key":"S0219720026510017BIB004","doi-asserted-by":"publisher","DOI":"10.3390\/cells12030490"},{"key":"S0219720026510017BIB005","doi-asserted-by":"publisher","DOI":"10.1126\/science.1218351"},{"key":"S0219720026510017BIB006","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.03.025"},{"key":"S0219720026510017BIB007","doi-asserted-by":"publisher","DOI":"10.1080\/15384101.2017.1403681"},{"key":"S0219720026510017BIB008","doi-asserted-by":"publisher","DOI":"10.1038\/msb.2011.20"},{"key":"S0219720026510017BIB009","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2008.03.016"},{"key":"S0219720026510017BIB010","doi-asserted-by":"publisher","DOI":"10.1038\/msb4100068"},{"key":"S0219720026510017BIB011","volume-title":"Principles of Automatic Control","author":"Shousong Hu","year":"2023","edition":"8"},{"key":"S0219720026510017BIB012","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.2.152"},{"key":"S0219720026510017BIB013","doi-asserted-by":"publisher","DOI":"10.7498\/aps.65.028701"},{"key":"S0219720026510017BIB014","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0507493103"},{"key":"S0219720026510017BIB015","doi-asserted-by":"publisher","DOI":"10.1126\/science.1092472"},{"key":"S0219720026510017BIB016","doi-asserted-by":"crossref","first-page":"100833","DOI":"10.1016\/j.drup.2022.100833","volume":"62","author":"Fukumoto RS","year":"2022","journal-title":"Drug Resist Updat"}],"container-title":["Journal of Bioinformatics and Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.worldscientific.com\/doi\/pdf\/10.1142\/S0219720026510017","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T02:59:13Z","timestamp":1772852353000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.worldscientific.com\/doi\/10.1142\/S0219720026510017"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2]]},"references-count":16,"journal-issue":{"issue":"01","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["10.1142\/S0219720026510017"],"URL":"https:\/\/doi.org\/10.1142\/s0219720026510017","relation":{},"ISSN":["0219-7200","1757-6334"],"issn-type":[{"value":"0219-7200","type":"print"},{"value":"1757-6334","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2]]},"article-number":"2651001"}}