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

TitleReplication Pauses of the Wild-Type and Mutant Mitochondrial DNA Polymerase Gamma: A Simulation Study
Publication TypeJournal Article
Year of Publication2011
AuthorsSong, Z., Y. Cao, and D. C. Samuels
JournalPLOS COMPUTATIONAL BIOLOGY
Volume7
Issue11
Date PublishedNOV
Type of ArticleArticle
ISSN1553-734X
Abstract

The 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.

DOI10.1371/journal.pcbi.1002287