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Updated: Jun 12, 2026
Visualizing and Quantifying Endonuclease-Based Site-Specific DNA Damage
Published on: August 21, 2021
Programmed cell death triggered by nucleotide pool damage and its prevention by MutT homolog-1 (MTH1) with oxidized
Yusaku Nakabeppu1, Sugako Oka, Zijing Sheng
1Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. yusaku@bioreg.kyushu-u.ac.jp
Abstract:
Accumulation of oxidized bases such as 8-oxoguanine in either nuclear or mitochondrial DNA triggers various cellular dysfunctions including mutagenesis, and programmed cell death or senescence. Recent studies have revealed that oxidized nucleoside triphosphates such as 8-oxo-dGTP in the nucleotide pool are the main source of oxidized bases accumulating in the DNA of cells under oxidative stress. To counteract such deleterious effects of nucleotide pool damage, mammalian cells possess MutT homolog-1 (MTH1) with oxidized purine nucleoside triphosphatase and related enzymes, thus minimizing the accumulation of oxidized bases in cellular DNA. Depletion or increased expression of the MTH1 protein have revealed its significant roles in avoiding programmed cell death or senescence as well as mutagenesis, and accumulating evidences indicate that MTH1 is involved in suppression of degenerative disorders such as neurodegeneration.
Insights
Oxidative stress damages DNA via oxidized bases. The MTH1 enzyme protects cells by eliminating damaged nucleotide triphosphates, preventing DNA mutations and cell death, and potentially treating neurodegeneration.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Oxidized bases like 8-oxoguanine in DNA cause cellular dysfunction, including mutagenesis and cell death.
- Oxidized nucleoside triphosphates (e.g., 8-oxo-dGTP) in the nucleotide pool are the primary source of DNA oxidation under stress.
Purpose of the Study:
- To investigate the protective role of MutT homolog-1 (MTH1) against DNA damage.
- To understand MTH1's function in preventing mutagenesis, cell death, and its implications in neurodegenerative diseases.
Main Methods:
- Analysis of MTH1 protein's oxidized purine nucleoside triphosphatase activity.
- Studies involving MTH1 protein depletion and overexpression in mammalian cells.
- Examination of cellular responses including mutagenesis, programmed cell death, and senescence.
Main Results:
- MTH1 effectively removes oxidized purine nucleoside triphosphates, minimizing oxidized bases in DNA.
- MTH1 plays a crucial role in preventing mutagenesis and programmed cell death/senescence.
- Evidence suggests MTH1's involvement in suppressing neurodegenerative disorders.
Conclusions:
- MTH1 is a key enzyme in cellular defense against oxidative DNA damage.
- MTH1's protective functions are vital for maintaining genomic stability and preventing cell death.
- MTH1 represents a potential therapeutic target for neurodegenerative diseases.
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