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

Megan Carter,Brent D G Page,Ann-Sofie Jemth,Robert Gustafsson,Thomas Helleday,Helge Gad,Nicholas C K Valerie,Pål Stenmark,Johan Boström,Matthieu Desroses,Anna Hagenkort,Ulrika Warpman Berglund,Julia J Griese

doi:10.1038/ncomms8871

Megan Carter, Brent D G Page + Show 11 more

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https://doi.org/10.1038/ncomms8871

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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.

Highlights

Deregulated redox metabolism in cancer leads to oxidative damage to cellular components including deoxyribonucleoside triphosphates
MTH1 is a major sanitizer of 8-oxo-dGTP and 2-OH-dATP
In the search for potential anticancer targets that sanitize the oxidized nucleotide pool, we investigated other MutT homologues with reported activity towards oxidized nucleotides

Summary

Introduction

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 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. Despite advances in targeted therapies and personalized medicine, DNA damaging treatments such as radio- and chemotherapy remain the primary anticancer treatment modality[1]. Altered metabolic and redox activities in cancer cells increase the production of reactive oxygen species that can cause DNA damage[4,5]. For cancer cells with deregulated reactive oxygen species, nucleotide pool sanitizing enzymes are critically important, as damaged dNTPs can be incorporated into the DNA inducing mutations and DNA damage. We sought to investigate other enzymes that sanitize the dNTP pool and determine whether these enzymes might be targeted to induce cancer phenotypic lethality or overcome resistance to MTH1 inhibitors

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