Abstract |
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.
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Authors | Megan Carter, Ann-Sofie Jemth, Anna Hagenkort, Brent D G Page, Robert Gustafsson, Julia J Griese, Helge Gad, Nicholas C K Valerie, Matthieu Desroses, Johan Boström, Ulrika Warpman Berglund, Thomas Helleday, Pål Stenmark |
Journal | Nature communications
(Nat Commun)
Vol. 6
Pg. 7871
(Aug 04 2015)
ISSN: 2041-1723 [Electronic] England |
PMID | 26238318
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Deoxyguanine Nucleotides
- Deoxyribonucleotides
- 8-oxodeoxyguanosine triphosphate
- NUDT15 protein, human
- Phosphoric Monoester Hydrolases
- Pyrophosphatases
- 8-oxodGTPase
- DNA Repair Enzymes
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Topics |
- Blotting, Western
- Cell Line, Tumor
- Cell Survival
- Crystallization
- DNA Repair Enzymes
(metabolism)
- Deoxyguanine Nucleotides
(metabolism)
- Deoxyribonucleotides
(metabolism)
- HCT116 Cells
- HeLa Cells
- Humans
- MCF-7 Cells
- Oxidation-Reduction
- Oxidative Stress
- Phosphoric Monoester Hydrolases
(metabolism)
- Pyrophosphatases
(chemistry, metabolism)
- Substrate Specificity
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