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MTH1, an 8-oxo-2'-deoxyguanosine triphosphatase, and MYH, a DNA glycosylase, cooperate to inhibit mutations induced by chronic exposure to oxidative stress of ionising 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.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
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Number of Authors: 62017 (English)In: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 32, no 3, p. 389-396Article in journal (Refereed) Published
Abstract [en]

Our previous results showed that in addition to the immediate interaction of ionising radiation with DNA (direct and indirect effect), low-dose and chronic low-dose rate of irradiation induce endogenous oxidative stress. During oxidative stress, free radicals react with DNA, nucleoside triphosphates (dNTPs), proteins and lipids, and modify their structures. The MYH and MTH1 genes play important roles in preventing mutations induced by 8-hydroxy-guanine, which is an oxidised product of guanine. In this study, we used short-hairpin RNA to permanently knockdown MYH and MTH1 proteins in human lymphoblastoid TK6 cells. Knockdown and wild-type cells were chronically exposed to low dose rates of gamma-radiation (between 1.4 and 30 mGy/h). The cells were also subjected to acute doses delivered at a high-dose rate. Growth rate, extracellular 8-hydroxy-2'-deoxyguanosine, clonogenic cell survival and mutant frequencies were analysed in all cell types. A reduced level of cell growth and survival as well as increased mutant frequencies were observed in cells lacking both MYH and MTH1 proteins as compared to cells lacking only MYH and wild-type cells. To sum up, our results suggest that low-dose rates elevate oxidative stress. MTH1 together with MYH plays an important role in protection against mutations induced by modified dNTPs during chronic oxidative stress. In addition, we found no dose-rate effect at the level of mutations in the wild-type TK6 and MYH-KD cells. Our data interestingly indicate a dose-rate threshold for mutation induction in MTH1/MYH double knockdown cells.

Place, publisher, year, edition, pages
2017. Vol. 32, no 3, p. 389-396
National Category
Biological Sciences
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URN: urn:nbn:se:su:diva-144714DOI: 10.1093/mutage/gex003ISI: 000400872500006OAI: oai:DiVA.org:su-144714DiVA, id: diva2:1127972
Available from: 2017-07-20 Created: 2017-07-20 Last updated: 2017-07-20Bibliographically approved

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Sangsuwan, TraimatePour Khavari, AliEmami, S. NoushinHaghdoost, Siamak
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