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Analysis of mutant frequencies and mutation spectra in hMTH1 knockdown TK6 cells exposed to UV radiation
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
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2013 (English)In: Mutation research, ISSN 0027-5107, E-ISSN 1873-135X, Vol. 751, 8-14 p.Article in journal (Refereed) Published
Abstract [en]

Ultraviolet radiation is a highly mutagenic agent that damages the DNA by the formation of mutagenic photoproducts at dipyrimidine sites and by oxidative DNA damages via reactive oxygen species (ROS). ROS can also give rise to mutations via oxidation of dNTPs in the nucleotide pool, e.g. 8-oxo-dGTP and 2-OH-dATP and subsequent incorporation during DNA replication. Here we show that expression of human MutT homolog 1 (hMTH1) which sanitizes the nucleotide pool by dephosphorylating oxidized dNTPs, protects against mutagenesis induced by long wave UVA light and by UVB light but not by short wave UVC light. Mutational spectra analyses of UVA-induced mutations at the endogenous Thymidine kinase gene in human lymphoblastoid cells revealed that hMTH1 mainly protects cells from transitions at GC and AT base pairs.

Place, publisher, year, edition, pages
2013. Vol. 751, 8-14 p.
Keyword [en]
Ultraviolet radiation, Oxidative stress, Nucleotide pool, hMTH1, 8-Oxo-dG, 2-OH-dA
National Category
Biological Sciences
Research subject
Molecular Genetics
Identifiers
URN: urn:nbn:se:su:diva-100126DOI: 10.1016/j.mrfmmm.2013.10.001ISI: 000328874500002OAI: oai:DiVA.org:su-100126DiVA: diva2:691245
Note

AuthorCount:9;

Available from: 2014-01-27 Created: 2014-01-27 Last updated: 2017-12-06Bibliographically approved
In thesis
1. The role of MTH1 in ultraviolet radiation-induced mutagenesis
Open this publication in new window or tab >>The role of MTH1 in ultraviolet radiation-induced mutagenesis
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Ultraviolet radiation (UVR) is known to be highly mutagenic. What types of DNA lesions that are induced by different UVR wavelengths are still a matter of debate. UVR induces mutagenesis mostly by the formation of photoproducts and the induction of reactive oxygen species (ROS). ROS can give rise to mutations via oxidation of nucleotides in the DNA or the nucleotide pool. Oxidized nucleotides in the nucleotide pool can thereby be incorporated into the DNA during replication and ultimately give rise to mutations. MTH1 however, dephosphorylates oxidized nucleotides in the nucleotide pool, in particular 8-oxo-dGTP and 2-OH-dATP, and inhibits their incorporation into the DNA.The aim of the present study was to investigate the role of MTH1 in mutagenesis and cytogenetic damage induced by UVR in a human lymphoblastoid TK6 cell line. The clonogenic survival, mutant frequency and micronucleus frequency were measured following exposure to UVA, UVB and UVC in MTH1-knockdown and wild-type TK6 cells. As a biomarker for oxidative damage the level of intracellular and extracellular 8-oxo-dG was measured in TK6 cells exposed to UVA. The mutational spectra of UVA-induced mutations at the thymidine kinase gene in MTH1-knockdown and wild-type TK6 cells were investigated.The results show that MTH1 protects against UVA and UVB mutagenesis significantly. MTH1, however, has been shown to offer no protection against UVR-induced cytogenetic damage and is therefore suggested to mainly inhibit mutagenesis. The mutational spectra show that GC>AT and AT>GC transitions are the dominant mutation types in cells exposed to UVA.In conclusion, MTH1 protects TK6 cells against mutagenesis induced by longer wavelengths of UVR. This indicates that the nucleotide pool is a significant target in mutagenesis for longer wavelengths of UVR. The type of mutations induced by UVA, GC>AT and AT>GC, can be formed by the incorporation of 2-OH-dATP from nucleotide pool into the DNA. UVA is therefore suggested to induce mutations by induction of oxidized nucleotides such as 2-OH-dATP.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2015. 46 p.
Keyword
ultraviolet radiation, MTH1, reactive oxygen species, 8-oxo-dGTP, 2-OH-dATP, micronucleus
National Category
Biological Sciences
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:su:diva-113320 (URN)978-91-7649-096-9 (ISBN)
Public defence
2015-03-06, William-Olssonsalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 10:00 (English)
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Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

Available from: 2015-02-12 Created: 2015-01-28 Last updated: 2016-11-02Bibliographically approved

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Fotouhi, AsalWojcik, AndrzejHarms-Ringdahl, MatsHaghdoost, Siamak
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