2. Academic Validation
  3. Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2

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

  • Nat Commun. 2015 Aug 4;6:7871. doi: 10.1038/ncomms8871.
Megan Carter 1,  Ann-Sofie Jemth 2,  Anna Hagenkort 2,  Brent D G Page 2,  Robert Gustafsson 1,  Julia J Griese 1,  Helge Gad 2,  Nicholas C K Valerie 2,  Matthieu Desroses 2,  Johan Boström 2,  Ulrika Warpman Berglund 2,  Thomas Helleday 2,  Pål Stenmark 1
Affiliations

Affiliations

  • 1 Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden.
  • 2 Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
PMID: 26238318 DOI: 10.1038/ncomms8871
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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