Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2

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 () and Pål Stenmark ()
Additional contact information
Megan Carter: Stockholm University
Ann-Sofie Jemth: Science for Life Laboratory, Karolinska Institutet
Anna Hagenkort: Science for Life Laboratory, Karolinska Institutet
Brent D. G. Page: Science for Life Laboratory, Karolinska Institutet
Robert Gustafsson: Stockholm University
Julia J. Griese: Stockholm University
Helge Gad: Science for Life Laboratory, Karolinska Institutet
Nicholas C. K. Valerie: Science for Life Laboratory, Karolinska Institutet
Matthieu Desroses: Science for Life Laboratory, Karolinska Institutet
Johan Boström: Science for Life Laboratory, Karolinska Institutet
Ulrika Warpman Berglund: Science for Life Laboratory, Karolinska Institutet
Thomas Helleday: Science for Life Laboratory, Karolinska Institutet
Pål Stenmark: Stockholm University

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8871

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