Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/86507
標題: A novel role of the tumor suppressor GNMT in cellular defense against DNA damage
作者: Wang, Yi-Cheng
Lin, Wei-Li
Lin, Yan-Jun
Tang, Feng-Yao
Chen, Yi-Ming
Chiang, En-Pei Isabel
關鍵字: glycine-N methyltransferase
nuclear folate metabolism
purine synthesis
pyrimidine synthesis
stable isotopic tracer studies
transmethylation metabolic kinetics
uracil misincorporation
Adenosine
Animals
Carbon Radioisotopes
Carcinoma, Hepatocellular
Cell Nucleus
Cells, Cultured
Chromatography, High Pressure Liquid
DNA Methylation
Dietary Supplements
Female
Fluorescent Antibody Technique, Indirect
Folic Acid
Glycine N-Methyltransferase
Hepatocytes
Homocysteine
Humans
Liver
Liver Neoplasms
Male
Methylenetetrahydrofolate Dehydrogenase (NADP)
Mice
Mice, Knockout
Protein Transport
Purines
Pyrimidines
S-Adenosylhomocysteine
S-Adenosylmethionine
Tetrahydrofolates
Uracil
DNA Damage
摘要: Glycine N-methyltransferase (GNMT) is a folate binding protein commonly diminished in human hepatoma yet its role in tumor development remains to be established. GNMT binds to methylfolate but is also inhibited by it; how such interactions affect human carcinogenesis is unclear. We postulated that GNMT plays a role in folate-dependent methyl group homeostasis and helps maintain genome integrity by promoting nucleotide biosynthesis and DNA repair. To test the hypothesis, GNMT was over-expressed in GNMT-null cell lines cultured in conditions of folate abundance or restriction. The partitioning of folate dependent 1-carbon groups was investigated using stable isotopic tracers and GC/MS. DNA damage was assessed as uracil content in cell models, as well as in Gnmt wildtype (Gnmt(+/+)), heterozygote (Gnmt(+/-)) and knockout (Gnmt(-/-)) mice under folate deplete, replete, or supplementation conditions. Our study demonstrated that GMMT 1) supports methylene-folate dependent pyrimidine synthesis; 2) supports formylfolate dependent purine syntheses; 3) minimizes uracil incorporation into DNA when cells and animals were exposed to folate depletion; 4) translocates into nuclei during prolonged folate depletion. In conclusion, loss of GNMT impairs nucleotide biosynthesis. Over-expression of GNMT enhances nucleotide biosynthesis and improves DNA integrity by reducing uracil misincorporation in DNA both in vitro and in vivo. To our best knowledge, the role of GNMT in folate dependent 1-carbon transfer in nucleotide biosynthesis has never been investigated. The present study gives new insights into the underlying mechanism by which GNMT can participate in tumor prevention/suppression in humans.
URI: http://hdl.handle.net/11455/86507
ISSN: 00207136
1097-0215
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