<b>MutT‐related error avoidance mechanism for DNA synthesis</b>

Sekiguchi, Mutsuo

doi:10.1046/j.1365-2443.1996.d01-232.x

Cited by 65 publications

(35 citation statements)

References 31 publications

(39 reference statements)

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“…As shown in Fig. 3, the six proteins identified biochemically are enzymes that hydrolyze dGTP or a mutagenic nucleotide, 8-oxo-dGTP (6,18). Over 10 putative homologs for bacterial MutT proteins, which also possess the 23-residue sequence and may hydrolyze 8-oxodGTP, can be retrieved by data base searching with the BLASTP alogrithm.…”

Section: Discussionmentioning

confidence: 99%

Functional Significance of the Conserved Residues for the 23-Residue Module among MTH1 and MutT Family Proteins

Fujii¹,

Shimokawa²,

Sekiguchi³

et al. 1999

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Functional Significance of the Conserved Residues for the 23-Residue Module among MTH1 and MutT Family Proteins

Fujii¹,

Shimokawa²,

Sekiguchi³

et al. 1999

Journal of Biological Chemistry

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“…Enzyme activities similar to those of the E. coli proteins were identified in mammalian cells (13)(14)(15). Among them, the MutT-related protein has been studied most extensively (16). Based on the partial amino acid sequence determined with the purified 18-kDa protein bearing 8-oxo-dGTPase activity, cDNA and the gene for the human enzyme were isolated and named as MTH1 (mutT homolog-1; refs.…”

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confidence: 99%

Spontaneous tumorigenesis in mice defective in the MTH1 gene encoding 8-oxo-dGTPase

Tsuzuki

Egashira

Igarashi

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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“…Enzymatic activities similar to that of MutT had been identified in both human and other mammalian cells (10 -13). Based on the similarity in their amino acid sequences to that of MutT and their catalytic activities hydrolyzing 8-oxo-dGTP, the proteins were named MTH1 (MutT homolog-1) (14). Because the expression of the mammalian enzymes in mutT Ϫ E. coli cells suppresses the elevated level of spontaneous mutagenesis to an almost normal level, MTH1 appears to have the same antimutagenic capacity as E. coli MutT (10,11,15).…”

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confidence: 99%

A Molecular Basis for the Selective Recognition of 2-Hydroxy-dATP and 8-Oxo-dGTP by Human MTH1

Sakai¹,

Furuichi²,

Takahashi³

et al. 2002

Journal of Biological Chemistry

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MTH1 hydrolyzes oxidized purine nucleoside triphosphates such as 8-oxo-dGTP, 8-oxo-dATP, 2-hydroxydATP, and 2-hydroxy rATP to monophosphates, and thus avoids errors caused by their misincorporation during DNA replication or transcription, which may result in carcinogenesis or neurodegeneration. This substrate specificity for oxidized purine nucleoside triphosphates was investigated by mutation analyses based on the sequence comparison with the Escherichia coli homolog, MutT, which hydrolyzes only 8-oxo-dGTP and 8-oxo-rGTP but not oxidized forms of dATP or ATP. Neither a replacement of the phosphohydrolase module of MTH1 with that of MutT nor deletions of the C-terminal region of MTH1, which is unique for MTH1, altered the substrate specificity of MTH1. In contrast, the substitution of residues at position Trp-117 and Asp-119 of MTH1, which showed apparent chemical shift perturbations with 8-oxo-dGDP in NMR analyses but are not conserved in MutT, affected the substrate specificity. Trp-117 is essential for MTH1 to recognize both 8-oxodGTP and 2-hydroxy-dATP, whereas Asp-119 is only essential for recognizing 2-hydroxy-dATP, thus suggesting that origins of the substrate-binding pockets for MTH1 and MutT are different.Endogenous oxidation of nucleic acids, such as DNA, RNA, and their precursors by reactive oxygen species generated under normal metabolic conditions, appear to induce spontaneous mutagenesis and cell death, which have been implicated in aging and various diseases including cancer and neuronal degeneration (1). It has been established that 8-oxoguanine (8-oxoG), an oxidized form of guanine, is highly mutagenic and one of the main endogenous sources for spontaneous mutagenesis. During DNA replication, 8-oxo-deoxyguanosine triphosphate (8-oxo-dGTP) can be inserted into the nascent strand opposite adenine and cytosine in the template, with almost equal efficiency, thus resulting in an A:T to C:G transversion mutation (2, 3). Accumulation of 8-oxoG in double-stranded DNA is caused by direct oxidization of guanine in DNA or incorporation of precursor nucleotide, 8-oxo-dGTP, which is generated in nucleotide pools with oxidation of dGTP (4). A misincorporation of oxidized nucleotides also occurs during transcription, thus leading to an accumulation of abnormal proteins (5, 6).To eliminate such deleterious oxidized nucleotides, organisms come equipped with elaborate mechanisms. In Escherichia coli the MutT protein hydrolyzes 8-oxo-dGTP and 8-oxoguanosine triphosphate (8-oxo-rGTP) to the monophosphate form, thus avoiding the misincorporation of mutagenic nucleotides into DNA and mRNA during replication and transcription (7,8). The absence of the mutT gene increases the spontaneous occurrence of A:T to C:G transversion a thousandfold over the wild type level (7, 9), and further increases the occurrence of transcriptional errors (6). Enzymatic activities similar to that of MutT had been identified in both human and other mammalian cells (10 -13). Based on the similarity in their amino acid sequences to that of Mut...

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MutT‐related error avoidance mechanism for DNA synthesis

Cited by 65 publications

References 31 publications

Functional Significance of the Conserved Residues for the 23-Residue Module among MTH1 and MutT Family Proteins

Functional Significance of the Conserved Residues for the 23-Residue Module among MTH1 and MutT Family Proteins

Spontaneous tumorigenesis in mice defective in the MTH1 gene encoding 8-oxo-dGTPase

A Molecular Basis for the Selective Recognition of 2-Hydroxy-dATP and 8-Oxo-dGTP by Human MTH1

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