MTH1: Effects on DNA Damage Repair, Cancer and Neurodegeneration

Mon, 02/03/2014 - 16:01

MTH1 (human MutT Homolog 1) is a purine nucleoside triphosphatase enzyme and belongs to the Nudix hydrolase family. In mammalian systems, MTH is a major detoxifier of the oxidized DNA precursors, 8-oxo-dGTP, 8-oxo-dATP, and 2-OH-dATP and prevents the misincorporation of these purine nucleoside triphosphates into DNA and the subsequent occurrence of A:T pairs to C:G and G:C to T:A pair transversions. The MTH enzyme can also hydrolyze the corresponding ribonucleotides, 8-oxo-GTP, 8-oxo-ATP, and 2-OH-ATP. It is antimutagenic and suppresses cell dysfunction and/or death induced by oxidative stress, and MTH1 deficiency increases cells’ susceptibility to oxidative damage-mediated dysfunction. The MTH1 enzyme is found mostly in the cytoplasm, but also in the nucleus and mitochondria, with highest expression levels in tissue types such as the thymus, testis, and embryo. In the types of oxidative DNA damage that occur during aging, cancer, and various neurodegenerative diseases (Parkinson's, Alzheimer's, and amyotrophic lateral sclerosis), both nuclear and mitochondrial genome accumulation of 8-oxoG is seen. Use of the MTH1 antibody allowed Rai, et al. at the Whitehead Institute to identify the guanine nucleotide pool as a critical target for oncogenic RAS-transformed cells via reactive oxygen species (ROS) (1). The MTH1 antibody also allowed the same group to demonstrate that oxidized nucleotides can rapidly induce cell senescence in a manner much like that of replicative senescence (2).  Takeshita’s group employed the MTH1 antibody in immunohistochemistry and immunoblotting experiments in the rat colon and mammary gland to contrast the effects of caffeine on PhIP-induced cancer (3).

Western Blot: MTH1 Antibody Western Blot: MTH1 Antibody

Another group comparing MTH expression levels in human lung cancers used similar techniques with the MTH1 antibody to develop protein expression profiles and possibly use MTH as a diagnostic marker for persistent oxidative stress (4). Sheng, et al. performed both immunohistochemistry and immunofluorescence with the MTH1 antibody to study the mechanism of how MUTYH-mediated DNA base excision repair (specifically of 8-oxo-dGTP) causes striatal neurodegeneration in mice neurons and microglia (5).

  1. PMID: 21076467
  2. PMID: 19118192
  3. PMID: 12706856
  4. PMID: 12757855
  5. PMID: 23143307

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