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Nature Research, Nature Communications, 1(6), 2015

DOI: 10.1038/ncomms8871

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

Journal article published in 2015 by Megan Carter, Ann-Sofie Jemth, Anna Hagenkort, Brent D. G. Page, Robert Gustafsson, Julia J. Griese ORCID, Helge Gad, Nicholas C. K. Valerie ORCID, Matthieu Desroses, Johan Boström, Ulrika Warpman Berglund ORCID, Ulrika Warpman Berglund, Thomas Helleday ORCID, Pål Stenmark
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

AbstractDeregulated 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.