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An involvement of mammalian MTH1 protein (8-oxo-dGTPase) in carcinogenesis and its potential utilization as a molecular marker of carcinogenesis and oxidative stress

Karol Białkowski 1Anna M. Szpila 1Kazimierz S. Kasprzak 2Ryszard S. Oliński 1

1. Nicolaus Copernicus University, Collegium Medicum , Department of Clinical Biochemistry, ul. Karlowicza 24, Bydgoszcz 85-092, Poland
2. National Cancer Institute at Frederick (NCI-NIH), Frederick 21702-1201, United States

Abstract

MTH1 protein is a pyrophosphohydrolase that degrades purine nucleoside 5'-triphosphates to the corresponding nucleoside 5'-monophosphate and inorganic pyrophosphate. The enzyme hydrolyzes most specifically some products of oxidative damage to 2'-deoxyguanosine 5'-triphosphate (dGTP) and 2'-deoxyadenosine 5'-triphosphate which are substrates for DNA synthesis. One of the best characterized mutagenic nucleotides is 8-oxo-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP) that likely forms in the cells under attack of reactive oxygen species (ROS). 8-Oxo-dGTP is an erroneous substrate for many DNA polymerases that incorporate this nucleotide (as monophosphate) to a nascent DNA strand during DNA replication. Such an incorporation causes point mutations during subsequent replication rounds due to mispairing properties of 8-oxo-dG that may form stable pairs with dC as well as with dA. As MTH1 protein hydrolyzes very effectively 8-oxo-dGTP and some other oxidized nucleotides, its widely accepted function is assigned to preventing point mutations by sanitization of these promutagenic compounds out of cellular free nucleotide pool. Mammalian mth1 genes are homologues of the first mutator gene (mutT) discovered in E. coli bacteria. A mutT strain of E. coli devoid of functional MutT protein exhibits very strong mutator phenotype characterized by 1000-fold higher frequency of AT→CG transversions. Once 8-oxo-dGTPase activity of MutT was identified to be responsible for antimutagenic effects of this protein, mammalian homologues of MutT attracted the attention of carcinogenesis investigators. An initial null mutation of mth1 gene in mammalian cell was anticipated to result in a mutator phenotype, a fast accumulation of mutations in the genomes of the progeny cells and their subsequent malignant transformation. However, such a mutation has not been observed to date in human cancers. Surprisingly, instead of mth1 disruption, an overexpression of the gene has been noticed in different cancer cells and tissues as compared with their healthy counterparts. These observations have led to formulation of the hypothesis that mth1 overexpression is a marker of carcinogenesis. Since mth1 upregulation has been most frequently assigned to a state of persistent oxidative stress in cancer cells, it has also been proposed that such overexpression might be a marker of the oxidative stress itself. Many investigators anticipate the existence of a cellular signaling mechanism that induces MTH1 in response to ROS to counteract the increased formation of oxidized purine nucleotides. However, the stimuli and signaling pathways that affect mth1 still remain largely unknown. The results of the studies performed in our laboratory that were devoted to the regulation of cellular 8-oxo-dGTPase activity of MTH1 protein will be presented and discussed in the context of its potential utilization as a marker of carcinogenesis and oxidative stress. RO, AS, and KB are partners of ECNIS (No 513943)

 

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Presentation: Wykład at Zjazd Polskiego Towarzystwa Biochemicznego, Sympozjum I, by Karol Białkowski
See On-line Journal of Zjazd Polskiego Towarzystwa Biochemicznego

Submitted: 2007-05-08 18:24
Revised:   2009-06-07 00:44