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Ogg1 knockout-associated lung tumorigenesis and its suppression by Mth1 gene disruption
Kunihiko Sakumi1, Yohei Tominaga, Masato Furuichi
1Division of Neurofunctional Genomics, Medical Institute of Bioregulation, Kyushu University and CREST, JST, Fukuoka 812-8582, Japan. sakumi@bioreg.kyushu-u.ac.jp
Abstract:
Using Mth1 and Ogg1 knockout mice, we evaluated the roles of these enzymes to prevent tumorigenesis and the accumulation of 8-oxoguanine (8-oxoG) in DNA. We found that lung adenoma/carcinoma spontaneously developed in Ogg1 knockout mice approximately 1.5 years after birth in which 8-oxoG was found to accumulate in their genomes. The mean number of tumors/mouse was 0.71 for the Ogg1 knockout mice, which was five times higher than that observed in wild-type mice (0.14). Although the accumulation of 8-oxoG was also confirmed in the Ogg1, Mth1 double knockout mice, we found no tumor in the lungs of these mice. This observation suggests that Mth1 gene disruption resulted in a suppression of the tumorigenesis caused by an Ogg1 deficiency.
Insights
Mice lacking the Ogg1 enzyme developed lung tumors due to DNA damage. However, when the Mth1 gene was also removed, tumor development was suppressed, indicating Mth1
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- DNA damage is a key factor in cancer development.
- Oxidative stress leads to DNA lesions like 8-oxoguanine (8-oxoG).
- DNA glycosylases, such as Ogg1 and Mth1, play roles in DNA repair.
Purpose of the Study:
- To investigate the roles of Ogg1 and Mth1 in preventing tumorigenesis.
- To examine the accumulation of 8-oxoG in DNA in knockout mouse models.
- To determine if Mth1 influences tumorigenesis caused by Ogg1 deficiency.
Main Methods:
- Utilizing Ogg1 and Mth1 knockout mouse models.
- Monitoring spontaneous tumor development over time.
- Quantifying 8-oxoG accumulation in mouse genomes.
Main Results:
- Ogg1 knockout mice spontaneously developed lung adenoma/carcinoma.
- Significant accumulation of 8-oxoG was observed in Ogg1 knockout mice.
- Mice lacking both Ogg1 and Mth1 showed no lung tumors despite 8-oxoG accumulation.
- Tumorigenesis in Ogg1 deficient mice was suppressed by Mth1 gene disruption.
Conclusions:
- Ogg1 deficiency leads to 8-oxoG accumulation and lung tumorigenesis.
- Mth1 plays a crucial role in suppressing Ogg1 deficiency-induced tumorigenesis.
- Targeting Mth1 may offer a therapeutic strategy for cancers associated with oxidative DNA damage.