AKIMASA ICHINOE
Department School of Medicine(Tokyo Women's Medical University Adachi Medical Center), School of Medicine Position Assistant Professor |
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Article types | Original article |
Language | English |
Peer review | Peer reviewed |
Title | Mutator phenotype of MUTYH-null mouse embryonic stem cells. |
Journal | Formal name:The Journal of biological chemistry Abbreviation:J Biol Chem ISSN code:00219258/1083351X |
Domestic / Foregin | Foregin |
Volume, Issue, Page | 278(40),pp.38121-38124 |
Author and coauthor | Seiki Hirano†, Yohei Tominaga, Akimasa Ichinoe, Yasuhiro Ushijima, Daisuke Tsuchimoto, Yoko Honda-Ohnishi, Toshio Ohtsubo, Kunihiko Sakumi, Yusaku Nakabeppu |
Publication date | 2003/10/03 |
Summary | To evaluate the antimutagenic role of a mammalian
mutY homolog, namely the Mutyh gene, which encodes adenine DNA glycosylase excising adenine misincorporated opposite 8-oxoguanine in the template DNA, we generated MUTYH-null mouse embryonic stem (ES) cells. In the MUTYH-null cells carrying no adenine DNA glycosylase activity, the spontaneous mutation rate increased 2-fold in comparison with wild type cells. The expression of wild type mMUTYH or mutant mMUTYH protein with amino acid substitutions at the proliferating cell nuclear antigen binding motif restored the increased spontaneous mutation rates of the MUTYH-null ES cells to the wild type level. The expression of a mutant mMUTYH protein with an amino acid substitution (G365D) that corresponds to a germ-line mutation (G382D) found in patients with multiple colorectal adenomas could not suppress the elevated spontaneous mutation rate of the MUTYH-null ES cells. Although the recombinant mMUTYH(G365D) purified from Escherichia coli cells had a substantial level of adenine DNA glycosylase activity as did wild type MUTYH, no adenine DNA glycosylase activity was detected in the MUTYHnull ES cells expressing the mMUTYH(G365D) mutant protein. The germ-line mutation (G382D) of the human MUTYH gene is therefore likely to be responsible for the occurrence of a mutator phenotype in these patients. |
DOI | 10.1074/jbc.C300316200 |