Replication Pauses of the Wild-Type and Mutant Mitochondrial DNA Polymerase Gamma: A Simulation Study

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dc.contributorVirginia Techen
dc.contributor.authorSong, Zhuoen
dc.contributor.authorCao, Yangen
dc.contributor.authorSamuels, David C.en
dc.contributor.departmentComputer Scienceen
dc.date.accessed2014-07-02en
dc.date.accessioned2014-07-03T17:33:15Zen
dc.date.available2014-07-03T17:33:15Zen
dc.date.issued2011-11-17en
dc.description.abstractThe activity of polymerase gamma is complicated, involving both correct and incorrect DNA polymerization events, exonuclease activity, and the disassociation of the polymerase: DNA complex. Pausing of pol-gamma might increase the chance of deletion and depletion of mitochondrial DNA. We have developed a stochastic simulation of pol-gamma that models its activities on the level of individual nucleotides for the replication of mtDNA. This method gives us insights into the pausing of two pol-gamma variants: the A467T substitution that causes PEO and Alpers syndrome, and the exonuclease deficient pol-gamma (exo(-)) in premature aging mouse models. To measure the pausing, we analyzed simulation results for the longest time for the polymerase to move forward one nucleotide along the DNA strand. Our model of the exo(-) polymerase had extremely long pauses, with a 30 to 300-fold increase in the time required for the longest single forward step compared to the wild-type, while the naturally occurring A467T variant showed at most a doubling in the length of the pauses compared to the wild-type. We identified the cause of these differences in the polymerase pausing time to be the number of disassociations occurring in each forward step of the polymerase.en
dc.description.sponsorshipThis work was funded by the NIH/NIGMS through grant GM073744. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en
dc.format.mimetypeapplication/pdfen
dc.identifier.citationSong Z, Cao Y, Samuels DC (2011) Replication Pauses of the Wild-Type and Mutant Mitochondrial DNA Polymerase Gamma: A Simulation Study. PLoS Comput Biol 7(11): e1002287. doi:10.1371/journal.pcbi.1002287en
dc.identifier.doihttps://doi.org/10.1371/journal.pcbi.1002287en
dc.identifier.issn1553-734Xen
dc.identifier.urihttp://hdl.handle.net/10919/49310en
dc.identifier.urlhttp://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1002287en
dc.language.isoen_USen
dc.publisherPublic Library of Scienceen
dc.rightsCreative Commons CC0 1.0 Universal Public Domain Dedicationen
dc.rights.urihttp://creativecommons.org/publicdomain/zero/1.0/en
dc.subjectBiochemical simulationsen
dc.subjectDNA replicationen
dc.subjectMitochondriaen
dc.subjectDNAen
dc.subjectMutationen
dc.subjectPoint mutationen
dc.subjectPolymerasesen
dc.subjectSimulation and modelingen
dc.titleReplication Pauses of the Wild-Type and Mutant Mitochondrial DNA Polymerase Gamma: A Simulation Studyen
dc.title.serialPlos Computational Biologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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