{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T02:30:11Z","timestamp":1772159411820,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1009847","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,2,23]],"date-time":"2022-02-23T00:00:00Z","timestamp":1645574400000}}],"reference-count":55,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T00:00:00Z","timestamp":1643328000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>The cell cycle of<jats:italic>Caulobacter crescentus<\/jats:italic>involves the polar morphogenesis and an asymmetric cell division driven by precise interactions and regulations of proteins, which makes<jats:italic>Caulobacter<\/jats:italic>an ideal model organism for investigating bacterial cell development and differentiation. The abundance of molecular data accumulated on<jats:italic>Caulobacter<\/jats:italic>motivates system biologists to analyze the complex regulatory network of cell cycle via quantitative modeling. In this paper, We propose a comprehensive model to accurately characterize the underlying mechanisms of cell cycle regulation based on the study of:<jats:bold>a)<\/jats:bold>chromosome replication and methylation;<jats:bold>b)<\/jats:bold>interactive pathways of five master regulatory proteins including DnaA, GcrA, CcrM, CtrA, and SciP, as well as novel consideration of their corresponding mRNAs;<jats:bold>c)<\/jats:bold>cell cycle-dependent proteolysis of CtrA through hierarchical protease complexes. The temporal dynamics of our simulation results are able to closely replicate an extensive set of experimental observations and capture the main phenotype of seven mutant strains of<jats:italic>Caulobacter crescentus<\/jats:italic>. Collectively, the proposed model can be used to predict phenotypes of other mutant cases, especially for nonviable strains which are hard to cultivate and observe. Moreover, the module of cyclic proteolysis is an efficient tool to study the metabolism of proteins with similar mechanisms.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1009847","type":"journal-article","created":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T18:35:52Z","timestamp":1643394952000},"page":"e1009847","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Modeling the temporal dynamics of master regulators and CtrA proteolysis in Caulobacter crescentus cell cycle"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4755-1593","authenticated-orcid":true,"given":"Chunrui","family":"Xu","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6088-2792","authenticated-orcid":true,"given":"Henry","family":"Hollis","sequence":"additional","affiliation":[]},{"given":"Michelle","family":"Dai","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0804-1061","authenticated-orcid":true,"given":"Xiangyu","family":"Yao","sequence":"additional","affiliation":[]},{"given":"Layne T.","family":"Watson","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9336-3748","authenticated-orcid":true,"given":"Yang","family":"Cao","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7321-8962","authenticated-orcid":true,"given":"Minghan","family":"Chen","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,1,28]]},"reference":[{"key":"pcbi.1009847.ref001","unstructured":"Light CJ. cis-2-Decenoic Acid Signaling and Dispersion in Pseudomonas aeruginosa: The Role of Dispersed Cells in Virulence and Pathogenesis. State University of New York at Binghamton; 2017."},{"issue":"44","key":"pcbi.1009847.ref002","doi-asserted-by":"crossref","first-page":"18985","DOI":"10.1073\/pnas.1014395107","article-title":"An essential transcription factor, SciP, enhances robustness of Caulobacter cell cycle regulation","volume":"107","author":"MH Tan","year":"2010","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"Pt 10","key":"pcbi.1009847.ref003","doi-asserted-by":"crossref","first-page":"2492","DOI":"10.1099\/mic.0.055285-0","article-title":"The Caulobacter crescentus ctrA P1 promoter is essential for the coordination of cell cycle events that prevent the overinitiation of DNA replication","volume":"158","author":"AT Schredl","year":"2012","journal-title":"Microbiology"},{"issue":"1","key":"pcbi.1009847.ref004","doi-asserted-by":"crossref","first-page":"e9","DOI":"10.1371\/journal.pcbi.0040009","article-title":"A quantitative study of the division cycle of Caulobacter crescentus stalked cells","volume":"4","author":"S Li","year":"2008","journal-title":"PLoS computational biology"},{"issue":"43","key":"pcbi.1009847.ref005","doi-asserted-by":"crossref","first-page":"17111","DOI":"10.1073\/pnas.0708112104","article-title":"A DNA methylation ratchet governs progression through a bacterial cell cycle","volume":"104","author":"J Collier","year":"2007","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"2","key":"pcbi.1009847.ref006","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1128\/JB.185.2.573-580.2003","article-title":"tmRNA is required for correct timing of DNA replication in Caulobacter crescentus","volume":"185","author":"KC Keiler","year":"2003","journal-title":"Journal of bacteriology"},{"issue":"2","key":"pcbi.1009847.ref007","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1038\/sj.emboj.7600927","article-title":"DnaA couples DNA replication and the expression of two cell cycle master regulators","volume":"25","author":"J Collier","year":"2006","journal-title":"The EMBO journal"},{"issue":"6","key":"pcbi.1009847.ref008","doi-asserted-by":"crossref","first-page":"3720","DOI":"10.1093\/nar\/gkt1352","article-title":"The functions of DNA methylation by CcrM in Caulobacter crescentus: a global approach","volume":"42","author":"D Gonzalez","year":"2014","journal-title":"Nucleic acids research"},{"issue":"31","key":"pcbi.1009847.ref009","doi-asserted-by":"crossref","first-page":"15661","DOI":"10.1073\/pnas.1906119116","article-title":"Asymmetric division yields progeny cells with distinct modes of regulating cell cycle-dependent chromosome methylation","volume":"116","author":"X Zhou","year":"2019","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"12","key":"pcbi.1009847.ref010","doi-asserted-by":"crossref","first-page":"e1001749","DOI":"10.1371\/journal.pbio.1001749","article-title":"Computational and genetic reduction of a cell cycle to its simplest, primordial components","volume":"11","author":"SM Murray","year":"2013","journal-title":"PLoS Biol"},{"issue":"1","key":"pcbi.1009847.ref011","doi-asserted-by":"crossref","first-page":"e1004831","DOI":"10.1371\/journal.pgen.1004831","article-title":"The global regulatory architecture of transcription during the Caulobacter cell cycle","volume":"11","author":"B Zhou","year":"2015","journal-title":"PLoS Genet"},{"issue":"44","key":"pcbi.1009847.ref012","doi-asserted-by":"crossref","first-page":"E6859","DOI":"10.1073\/pnas.1614795113","article-title":"Dynamic translation regulation in Caulobacter cell cycle control","volume":"113","author":"JM Schrader","year":"2016","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"8","key":"pcbi.1009847.ref013","doi-asserted-by":"crossref","first-page":"e1000463","DOI":"10.1371\/journal.pcbi.1000463","article-title":"Temporal controls of the asymmetric cell division cycle in Caulobacter crescentus","volume":"5","author":"S Li","year":"2009","journal-title":"PLoS Comput Biol"},{"issue":"43","key":"pcbi.1009847.ref014","doi-asserted-by":"crossref","first-page":"16602","DOI":"10.1073\/pnas.0808807105","article-title":"A bacterial control circuit integrates polar localization and proteolysis of key regulatory proteins with a phospho-signaling cascade","volume":"105","author":"AA Iniesta","year":"2008","journal-title":"PNAS"},{"issue":"3","key":"pcbi.1009847.ref015","doi-asserted-by":"crossref","first-page":"035007","DOI":"10.1088\/1478-3975\/13\/3\/035007","article-title":"A stochastic spatiotemporal model of a response-regulator network in the Caulobacter crescentus cell cycle","volume":"13","author":"F Li","year":"2016","journal-title":"Physical biology"},{"key":"pcbi.1009847.ref016","doi-asserted-by":"crossref","unstructured":"Chen M, Li F, Subramanian K, Tyson J, Cao Y. Two-dimensional model of bipolar PopZ polymerization in caulobacter crescentus. In: Proceedings of the 6th ACM Conference on Bioinformatics, Computational Biology and Health Informatics; 2015. p. 37\u201346.","DOI":"10.1145\/2808719.2808723"},{"key":"pcbi.1009847.ref017","doi-asserted-by":"crossref","unstructured":"Xu C, Cao Y. A spatiotemporal model of polarity and spatial gradient establishment in caulobacter crescentus. 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Iniesta","year":"2006","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"9","key":"pcbi.1009847.ref026","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/j.resmic.2009.09.006","article-title":"The role of proteolysis in the Caulobacter crescentus cell cycle and development","volume":"160","author":"U Jenal","year":"2009","journal-title":"Research in microbiology"},{"issue":"2","key":"pcbi.1009847.ref027","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.cell.2015.09.030","article-title":"An adaptor hierarchy regulates proteolysis during a bacterial cell cycle","volume":"163","author":"KK Joshi","year":"2015","journal-title":"Cell"},{"key":"pcbi.1009847.ref028","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1146\/annurev.genet.40.110405.090423","article-title":"Mechanisms of cyclic-di-GMP signaling in bacteria","volume":"40","author":"U Jenal","year":"2006","journal-title":"Annu Rev 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bacteriology"},{"issue":"5","key":"pcbi.1009847.ref035","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/S1097-2765(00)80379-2","article-title":"Differential localization of two histidine kinases controlling bacterial cell differentiation","volume":"4","author":"RT Wheeler","year":"1999","journal-title":"Molecular cell"},{"issue":"17","key":"pcbi.1009847.ref036","doi-asserted-by":"crossref","first-page":"4420","DOI":"10.1093\/emboj\/cdf454","article-title":"A dynamically localized histidine kinase controls the asymmetric distribution of polar pili proteins","volume":"21","author":"PH Viollier","year":"2002","journal-title":"The EMBO Journal"},{"issue":"1","key":"pcbi.1009847.ref037","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1073\/pnas.86.1.119","article-title":"Rate, origin, and bidirectionality of Caulobacter chromosome replication as determined by pulsed-field gel electrophoresis","volume":"86","author":"A Dingwall","year":"1989","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"4","key":"pcbi.1009847.ref038","doi-asserted-by":"crossref","first-page":"e00170","DOI":"10.1128\/mSystems.00170-19","article-title":"Absolute Measurements of mRNA Translation in Caulobacter crescentus Reveal Important Fitness Costs of Vitamin B12 Scavenging","volume":"4","author":"JR Aretakis","year":"2019","journal-title":"mSystems"},{"issue":"2","key":"pcbi.1009847.ref039","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1109\/4235.996017","article-title":"A fast and elitist multiobjective genetic algorithm: NSGA-II","volume":"6","author":"K Deb","year":"2002","journal-title":"IEEE transactions on evolutionary computation"},{"key":"pcbi.1009847.ref040","doi-asserted-by":"crossref","unstructured":"Chang TH, Watson LT, Larson J, Neveu N, Thacker W, Deshpande S, et al. Algorithm XXXX: VTMOP: Solver for Blackbox Multiobjective Optimization Problems. 2021, In press;.","DOI":"10.1145\/3529258"},{"issue":"3","key":"pcbi.1009847.ref041","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1145\/1527286.1527291","article-title":"Algorithm 897: VTDIRECT95: serial and parallel codes for the global optimization algorithm DIRECT","volume":"36","author":"J He","year":"2009","journal-title":"ACM Transactions on Mathematical Software (TOMS)"},{"key":"pcbi.1009847.ref042","unstructured":"Amos BD, Easterling DR, Watson LT, Thacker WI, Castle BS, Trosset MW. Algorithm XXX: QNSTOP\u2014quasi-Newton algorithm for stochastic optimization. Department of Computer Science, Virginia Polytechnic Institute & State \u2026; 2014."},{"issue":"1","key":"pcbi.1009847.ref043","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1109\/TCBB.2017.2773083","article-title":"Quasi-Newton stochastic optimization algorithm for parameter estimation of a stochastic model of the budding yeast cell cycle","volume":"16","author":"M Chen","year":"2017","journal-title":"IEEE\/ACM transactions on computational biology and bioinformatics"},{"issue":"3","key":"pcbi.1009847.ref044","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.cell.2005.12.033","article-title":"A Dynamically Localized Protease Complex and a Polar Specificity Factor Control a Cell Cycle Master Regulator","volume":"124","author":"PT McGrath","year":"2006","journal-title":"Cell"},{"issue":"4","key":"pcbi.1009847.ref045","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1016\/j.molcel.2011.07.018","article-title":"Regulatory cohesion of cell cycle and 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