Replication pauses of the wild-type and mutant mitochondrial DNA polymerase gamma: a simulation study.

The activity of polymerase γ is complicated, involving both correct and incorrect DNA polymerization events, exonuclease activity, and the disassociation of the polymerase:DNA complex. Pausing of pol-γ might increase the chance of deletion and depletion of mitochondrial DNA. We have developed a stoc...

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Autores principales:	Zhuo Song, Yang Cao, David C Samuels
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/8611fe1b6c224399a07f61abcf58b80d
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spelling	oai:doaj.org-article:8611fe1b6c224399a07f61abcf58b80d2021-11-18T05:51:46ZReplication pauses of the wild-type and mutant mitochondrial DNA polymerase gamma: a simulation study.1553-734X1553-735810.1371/journal.pcbi.1002287https://doaj.org/article/8611fe1b6c224399a07f61abcf58b80d2011-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22125488/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358The activity of polymerase γ is complicated, involving both correct and incorrect DNA polymerization events, exonuclease activity, and the disassociation of the polymerase:DNA complex. Pausing of pol-γ might increase the chance of deletion and depletion of mitochondrial DNA. We have developed a stochastic simulation of pol-γ 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-γ variants: the A467T substitution that causes PEO and Alpers syndrome, and the exonuclease deficient pol-γ (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.Zhuo SongYang CaoDavid C SamuelsPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 7, Iss 11, p e1002287 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Zhuo Song Yang Cao David C Samuels Replication pauses of the wild-type and mutant mitochondrial DNA polymerase gamma: a simulation study.
description	The activity of polymerase γ is complicated, involving both correct and incorrect DNA polymerization events, exonuclease activity, and the disassociation of the polymerase:DNA complex. Pausing of pol-γ might increase the chance of deletion and depletion of mitochondrial DNA. We have developed a stochastic simulation of pol-γ 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-γ variants: the A467T substitution that causes PEO and Alpers syndrome, and the exonuclease deficient pol-γ (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.
format	article
author	Zhuo Song Yang Cao David C Samuels
author_facet	Zhuo Song Yang Cao David C Samuels
author_sort	Zhuo Song
title	Replication pauses of the wild-type and mutant mitochondrial DNA polymerase gamma: a simulation study.
title_short	Replication pauses of the wild-type and mutant mitochondrial DNA polymerase gamma: a simulation study.
title_full	Replication pauses of the wild-type and mutant mitochondrial DNA polymerase gamma: a simulation study.
title_fullStr	Replication pauses of the wild-type and mutant mitochondrial DNA polymerase gamma: a simulation study.
title_full_unstemmed	Replication pauses of the wild-type and mutant mitochondrial DNA polymerase gamma: a simulation study.
title_sort	replication pauses of the wild-type and mutant mitochondrial dna polymerase gamma: a simulation study.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/8611fe1b6c224399a07f61abcf58b80d
work_keys_str_mv	AT zhuosong replicationpausesofthewildtypeandmutantmitochondrialdnapolymerasegammaasimulationstudy AT yangcao replicationpausesofthewildtypeandmutantmitochondrialdnapolymerasegammaasimulationstudy AT davidcsamuels replicationpausesofthewildtypeandmutantmitochondrialdnapolymerasegammaasimulationstudy
_version_	1718424740968792064

Replication pauses of the wild-type and mutant mitochondrial DNA polymerase gamma: a simulation study.

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