原创力文档replication pauses of the wild-type and mutant mitochondrial dna polymerase gamma a simulation study复制停顿的野生型和突变体线粒体dna聚合酶伽马仿真研究.pdfVIP
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replication pauses of the wild-type and mutant mitochondrial dna polymerase gamma a simulation study复制停顿的野生型和突变体线粒体dna聚合酶伽马仿真研究
Replication Pauses of the Wild-Type and Mutant
Mitochondrial DNA Polymerase Gamma: A Simulation
Study
1 2 1
Zhuo Song , Yang Cao , David C. Samuels *
1 Center for Human Genetic Research, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America, 2 Department of Computer Science, Virginia
Tech, Blacksburg, Virginia, United States of America
Abstract
The activity of polymerase c is complicated, involving both correct and incorrect DNA polymerization events, exonuclease
activity, and the disassociation of the polymerase:DNA complex. Pausing of pol-c might increase the chance of deletion and
depletion of mitochondrial DNA. We have developed a stochastic simulation of pol-c 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-c variants: the
A467T substitution that causes PEO and Alpers syndrome, and the exonuclease deficient pol-c (exo2) 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 exo2 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.
Citation: Song 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.1002287
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