MTH1 as a nucleotide pool sanitizing enzyme

Friend or foe?

Yusaku Nakabeppu, Eiko Ohta, Nona Abolhassani

Research output: Contribution to journalReview article

15 Citations (Scopus)

Abstract

8-Oxo-7,8-dihydroguanine (GO) can originate as 8-oxo-7,8-dihydro-2′-deoxyguanosine 5′-triphosphate (8-oxo-dGTP), an oxidized form of dGTP in the nucleotide pool, or by direct oxidation of guanine base in DNA. Accumulation of GO in cellular genomes can result in mutagenesis or programmed cell death, and is thus minimized by the actions of MutT homolog-1 (MTH1) with 8-oxo-dGTPase, OGG1 with GO DNA glycosylase and MutY homolog (MUTYH) with adenine DNA glycosylase. Studies on Mth1/Ogg1/Mutyh-triple knockout mice demonstrated that the defense systems efficiently minimize GO accumulation in cellular genomes, and thus maintain low incidences of spontaneous mutagenesis and tumorigenesis. Mth1/Ogg1-double knockout mice increased GO accumulation in the genome, but exhibited little susceptibility to spontaneous tumorigenesis, thus revealing that accumulation of GO in cellular genomes induces MUTYH-dependent cell death. Cancer cells are exposed to high oxidative stress levels and accumulate a high level of 8-oxo-dGTP in their nucleotide pools; cancer cells consequently express increased levels of MTH1 to eliminate 8-oxo-dGTP, indicating that increased expression of MTH1 in cancer cells may be detrimental for cancer patients. Mth1/Ogg1-double knockout mice are highly vulnerable to neurodegeneration under oxidative conditions, while transgenic expression of human MTH1 efficiently prevents neurodegeneration by avoiding GO accumulation in mitochondrial genomes of neurons and/or nuclear genomes of microglia, indicating that increased expression of MTH1 may be beneficial for neuronal tissues.

Original languageEnglish
Pages (from-to)151-158
Number of pages8
JournalFree Radical Biology and Medicine
Volume107
DOIs
Publication statusPublished - Jun 1 2017

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Nucleotides
Genes
Genome
Knockout Mice
DNA Glycosylases
Enzymes
Mutagenesis
Cells
Cell death
Neoplasms
Carcinogenesis
Cell Death
Mitochondrial Genome
Guanine
Microglia
Oxidative stress
Adenine
Oxidative Stress
Neurons
Tissue

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

Cite this

MTH1 as a nucleotide pool sanitizing enzyme : Friend or foe? / Nakabeppu, Yusaku; Ohta, Eiko; Abolhassani, Nona.

In: Free Radical Biology and Medicine, Vol. 107, 01.06.2017, p. 151-158.

Research output: Contribution to journalReview article

Nakabeppu, Yusaku ; Ohta, Eiko ; Abolhassani, Nona. / MTH1 as a nucleotide pool sanitizing enzyme : Friend or foe?. In: Free Radical Biology and Medicine. 2017 ; Vol. 107. pp. 151-158.
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