The GT to GC single nucleotide polymorphism at the beginning of an alternative exon 2C of human MTH1 gene confers an amino terminal extension that functions as a mitochondrial targeting signal

Yasunari Sakai, Hisanobu Oda, Daisuke Yoshimura, Masato Furuichi, Dongchon Kang, Shigenori Iwai, Toshiro Hara, Yusaku Nakabeppu

研究成果: ジャーナルへの寄稿記事

8 引用 (Scopus)

抄録

Human MTH1 protein hydrolyzes oxidized purine nucleotides 8-oxo-2′-deoxyguanosine triphosphate (8-oxo-dGTP), 2-OH-dATP or their ribo-forms to their monophosphates, thus minimizing replicational and transcriptional errors both in the nuclei and mitochondria. MTH1 suppresses mitochondrial dysfunction and cell death caused by H2O2. Furthermore, MTH1 suppresses the transient increase in 8-oxoguanine in mitochondrial DNA in the dopaminergic nerve terminals in mouse striatum after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration, and it protects the nerve terminals. We previously reported that a novel MTH1 allele with a single nucleotide polymorphism (SNP) in its exon 2c segment encodes the fourth MTH1 isoform, namely, MTH1a (p26), in addition to the three known isoforms, MTH1b (p22), c (p21), and d (p18). Another SNP located in exon 4 of the MTH1 gene, which is closely linked to the SNP in exon 2c, substitutes the Val83 residue in MTH1d with Met83. We herein show that all MTH1 isoforms efficiently hydrolyzed 2-OH-dATP and 8-oxo-dGTP. The amino terminal region of MTH1a functioned as a mitochondrial targeting signal when it was expressed in the HeLa cells as a fusion protein with enhanced green fluorescent protein. The cellular fractionation revealed that MTH1a(Met83) was localized in the mitochondria to the same extent as was MTH1d(Val83). However, the mitochondrial translocation of MTH1d(Met83) was less efficient than that of MTH1d(Val83).

元の言語英語
ページ(範囲)660-670
ページ数11
ジャーナルJournal of Molecular Medicine
84
発行部数8
DOI
出版物ステータス出版済み - 8 1 2006

Fingerprint

Single Nucleotide Polymorphism
Exons
Protein Isoforms
Mitochondria
Genes
Purine Nucleotides
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Mitochondrial DNA
HeLa Cells
Cell Death
Alleles
Proteins
8-oxo-7-hydrodeoxyguanosine
hydroxide ion
2-hydroxydeoxyadenosine triphosphate
deoxyguanosine triphosphate
enhanced green fluorescent protein
8-oxodGTPase
Protect-It
8-hydroxyguanine

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

これを引用

@article{307ecf05d0b24f629a683f4bb2ac8ad0,
title = "The GT to GC single nucleotide polymorphism at the beginning of an alternative exon 2C of human MTH1 gene confers an amino terminal extension that functions as a mitochondrial targeting signal",
abstract = "Human MTH1 protein hydrolyzes oxidized purine nucleotides 8-oxo-2′-deoxyguanosine triphosphate (8-oxo-dGTP), 2-OH-dATP or their ribo-forms to their monophosphates, thus minimizing replicational and transcriptional errors both in the nuclei and mitochondria. MTH1 suppresses mitochondrial dysfunction and cell death caused by H2O2. Furthermore, MTH1 suppresses the transient increase in 8-oxoguanine in mitochondrial DNA in the dopaminergic nerve terminals in mouse striatum after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration, and it protects the nerve terminals. We previously reported that a novel MTH1 allele with a single nucleotide polymorphism (SNP) in its exon 2c segment encodes the fourth MTH1 isoform, namely, MTH1a (p26), in addition to the three known isoforms, MTH1b (p22), c (p21), and d (p18). Another SNP located in exon 4 of the MTH1 gene, which is closely linked to the SNP in exon 2c, substitutes the Val83 residue in MTH1d with Met83. We herein show that all MTH1 isoforms efficiently hydrolyzed 2-OH-dATP and 8-oxo-dGTP. The amino terminal region of MTH1a functioned as a mitochondrial targeting signal when it was expressed in the HeLa cells as a fusion protein with enhanced green fluorescent protein. The cellular fractionation revealed that MTH1a(Met83) was localized in the mitochondria to the same extent as was MTH1d(Val83). However, the mitochondrial translocation of MTH1d(Met83) was less efficient than that of MTH1d(Val83).",
author = "Yasunari Sakai and Hisanobu Oda and Daisuke Yoshimura and Masato Furuichi and Dongchon Kang and Shigenori Iwai and Toshiro Hara and Yusaku Nakabeppu",
year = "2006",
month = "8",
day = "1",
doi = "10.1007/s00109-006-0053-5",
language = "English",
volume = "84",
pages = "660--670",
journal = "Clinical Investigator",
issn = "0946-2716",
publisher = "Springer Verlag",
number = "8",

}

TY - JOUR

T1 - The GT to GC single nucleotide polymorphism at the beginning of an alternative exon 2C of human MTH1 gene confers an amino terminal extension that functions as a mitochondrial targeting signal

AU - Sakai, Yasunari

AU - Oda, Hisanobu

AU - Yoshimura, Daisuke

AU - Furuichi, Masato

AU - Kang, Dongchon

AU - Iwai, Shigenori

AU - Hara, Toshiro

AU - Nakabeppu, Yusaku

PY - 2006/8/1

Y1 - 2006/8/1

N2 - Human MTH1 protein hydrolyzes oxidized purine nucleotides 8-oxo-2′-deoxyguanosine triphosphate (8-oxo-dGTP), 2-OH-dATP or their ribo-forms to their monophosphates, thus minimizing replicational and transcriptional errors both in the nuclei and mitochondria. MTH1 suppresses mitochondrial dysfunction and cell death caused by H2O2. Furthermore, MTH1 suppresses the transient increase in 8-oxoguanine in mitochondrial DNA in the dopaminergic nerve terminals in mouse striatum after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration, and it protects the nerve terminals. We previously reported that a novel MTH1 allele with a single nucleotide polymorphism (SNP) in its exon 2c segment encodes the fourth MTH1 isoform, namely, MTH1a (p26), in addition to the three known isoforms, MTH1b (p22), c (p21), and d (p18). Another SNP located in exon 4 of the MTH1 gene, which is closely linked to the SNP in exon 2c, substitutes the Val83 residue in MTH1d with Met83. We herein show that all MTH1 isoforms efficiently hydrolyzed 2-OH-dATP and 8-oxo-dGTP. The amino terminal region of MTH1a functioned as a mitochondrial targeting signal when it was expressed in the HeLa cells as a fusion protein with enhanced green fluorescent protein. The cellular fractionation revealed that MTH1a(Met83) was localized in the mitochondria to the same extent as was MTH1d(Val83). However, the mitochondrial translocation of MTH1d(Met83) was less efficient than that of MTH1d(Val83).

AB - Human MTH1 protein hydrolyzes oxidized purine nucleotides 8-oxo-2′-deoxyguanosine triphosphate (8-oxo-dGTP), 2-OH-dATP or their ribo-forms to their monophosphates, thus minimizing replicational and transcriptional errors both in the nuclei and mitochondria. MTH1 suppresses mitochondrial dysfunction and cell death caused by H2O2. Furthermore, MTH1 suppresses the transient increase in 8-oxoguanine in mitochondrial DNA in the dopaminergic nerve terminals in mouse striatum after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration, and it protects the nerve terminals. We previously reported that a novel MTH1 allele with a single nucleotide polymorphism (SNP) in its exon 2c segment encodes the fourth MTH1 isoform, namely, MTH1a (p26), in addition to the three known isoforms, MTH1b (p22), c (p21), and d (p18). Another SNP located in exon 4 of the MTH1 gene, which is closely linked to the SNP in exon 2c, substitutes the Val83 residue in MTH1d with Met83. We herein show that all MTH1 isoforms efficiently hydrolyzed 2-OH-dATP and 8-oxo-dGTP. The amino terminal region of MTH1a functioned as a mitochondrial targeting signal when it was expressed in the HeLa cells as a fusion protein with enhanced green fluorescent protein. The cellular fractionation revealed that MTH1a(Met83) was localized in the mitochondria to the same extent as was MTH1d(Val83). However, the mitochondrial translocation of MTH1d(Met83) was less efficient than that of MTH1d(Val83).

UR - http://www.scopus.com/inward/record.url?scp=33746676294&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33746676294&partnerID=8YFLogxK

U2 - 10.1007/s00109-006-0053-5

DO - 10.1007/s00109-006-0053-5

M3 - Article

VL - 84

SP - 660

EP - 670

JO - Clinical Investigator

JF - Clinical Investigator

SN - 0946-2716

IS - 8

ER -