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dc.contributor.authorAlnajjar, Khadijeh S
dc.contributor.authorKrylov, Ivan S
dc.contributor.authorNegahbani, Amirsoheil
dc.contributor.authorHaratipour, Pouya
dc.contributor.authorKashemirov, Boris A
dc.contributor.authorHuang, Ji
dc.contributor.authorMahmoud, Mariam
dc.contributor.authorMcKenna, Charles E
dc.contributor.authorGoodman, Myron F
dc.contributor.authorSweasy, Joann B
dc.date.accessioned2020-09-05T00:37:59Z
dc.date.available2020-09-05T00:37:59Z
dc.date.issued2019-11-16
dc.identifier.citationKhadijeh S Alnajjar, Ivan S Krylov, Amirsoheil Negahbani, Pouya Haratipour, Boris A Kashemirov, Ji Huang, Mariam Mahmoud, Charles E McKenna, Myron F Goodman, Joann B Sweasy, A pre-catalytic non-covalent step governs DNA polymerase β fidelity, Nucleic Acids Research, Volume 47, Issue 22, 16 December 2019, Pages 11839–11849, https://doi.org/10.1093/nar/gkz1076en_US
dc.identifier.issn0305-1048
dc.identifier.pmid31732732
dc.identifier.doi10.1093/nar/gkz1076
dc.identifier.urihttp://hdl.handle.net/10150/642582
dc.description.abstractDNA polymerase beta (pol beta) selects the correct deoxyribonucleoside triphosphate for incorporation into the DNA polymer. Mistakes made by pol beta lead to mutations, some of which occur within specific sequence contexts to generate mutation hotspots. The adenomatous polyposis coli (APC) gene is mutated within specific sequence contexts in colorectal carcinomas but the underlying mechanism is not fully understood. In previous work, we demonstrated that a somatic colon cancer variant of pol beta, K289M, misincorporates deoxynucleotides at significantly increased frequencies over wild-type pol beta within a mutation hotspot that is present several times within the APC gene. Kinetic studies provide evidence that the rate-determining step of pol beta catalysis is phosphodiester bond formation and suggest that substrate selection is governed at this step. Remarkably, we show that, unlike WT, a pre-catalytic step in the K289M pol beta kinetic pathway becomes slower than phosphodiester bond formation with the APC DNA sequence but not with a different DNA substrate. Based on our studies, we propose that precatalytic conformational changes are of critical importance for DNA polymerase fidelity within specific DNA sequence contexts.en_US
dc.language.isoenen_US
dc.publisherOXFORD UNIV PRESSen_US
dc.rightsCopyright © The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.en_US
dc.titleA pre-catalytic non-covalent step governs DNA polymerase β fidelityen_US
dc.typeArticleen_US
dc.contributor.departmentUniv Arizona, Canc Ctr,en_US
dc.contributor.departmentUniv Arizona, Dept Cellular & Mol Meden_US
dc.identifier.journalNUCLEIC ACIDS RESEARCHen_US
dc.description.noteOpen access journalen_US
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en_US
dc.eprint.versionFinal published versionen_US
dc.source.journaltitleNucleic acids research
dc.source.volume47
dc.source.issue22
dc.source.beginpage11839
dc.source.endpage11849
refterms.dateFOA2020-09-05T00:37:59Z
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryEngland


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