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Crystal structure, ...
Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2
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- Carter, Megan (author)
- Stockholms universitet,Institutionen för biokemi och biofysik,Stockholms universitet, Institutionen för biokemi och biofysik
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- Jemth, Ann-Sofie (author)
- Karolinska Institutet
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- Hagenkort, Anna (author)
- Karolinska Institutet
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- Page, Brent D. G. (author)
- Karolinska Institutet
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- Gustafsson, Robert (author)
- Stockholms universitet,Institutionen för biokemi och biofysik,Stockholms universitet, Institutionen för biokemi och biofysik
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- Griese, Julia J. (author)
- Stockholms universitet,Institutionen för biokemi och biofysik,Stockholms universitet, Institutionen för biokemi och biofysik
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- Gad, Helge (author)
- Karolinska Institutet
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- Valerie, Nicholas C. K. (author)
- Karolinska Institutet
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- Desroses, Matthieu (author)
- Karolinska Institutet
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- Boström, Johan (author)
- Karolinska Institutet
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- Berglund, Ulrika Warpman (author)
- Karolinska Institutet
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- Helleday, Thomas (author)
- Karolinska Institutet
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- Stenmark, Pål (author)
- Stockholms universitet,Institutionen för biokemi och biofysik,Stockholms universitet, Institutionen för biokemi och biofysik
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(creator_code:org_t)
- 2015-08-04
- 2015
- English.
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Abstract
Subject headings
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- Deregulated redox metabolism in cancer leads to oxidative damage to cellular components including deoxyribonucleoside triphosphates (dNTPs). Targeting dNTP pool sanitizing enzymes, such as MTH1, is a highly promising anticancer strategy. The MTH2 protein, known as NUDT15, is described as the second human homologue of bacterial MutT with 8-oxo-dGTPase activity. We present the first NUDT15 crystal structure and demonstrate that NUDT15 prefers other nucleotide substrates over 8-oxo-dGTP. Key structural features are identified that explain different substrate preferences for NUDT15 and MTH1. We find that depletion of NUDT15 has no effect on incorporation of 8-oxo-dGTP into DNA and does not impact cancer cell survival in cell lines tested. NUDT17 and NUDT18 were also profiled and found to have far less activity than MTH1 against oxidized nucleotides. We show that NUDT15 is not a biologically relevant 8-oxo-dGTPase, and that MTH1 is the most prominent sanitizer of the cellular dNTP pool known to date.
Subject headings
- NATURVETENSKAP -- Annan naturvetenskap (hsv//swe)
- NATURAL SCIENCES -- Other Natural Sciences (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Carter, Megan
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Jemth, Ann-Sofie
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Hagenkort, Anna
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Page, Brent D. G ...
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Gustafsson, Robe ...
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Griese, Julia J.
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show more...
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Gad, Helge
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Valerie, Nichola ...
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Desroses, Matthi ...
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Boström, Johan
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Berglund, Ulrika ...
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Helleday, Thomas
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Stenmark, Pål
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show less...
- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Other Natural Sc ...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
- Articles in the publication
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Nature Communica ...
- By the university
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Uppsala University
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Stockholm University
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Karolinska Institutet