量研学術機関リポジトリ「QST-Repository」は、国立研究開発法人 量子科学技術研究開発機構に所属する職員等が生み出した学術成果（学会誌発表論文、学会発表、研究開発報告書、特許等）を集積しインターネット上で広く公開するサービスです。 Welcome to QST-Repository where we accumulates and discloses the academic research results(Journal Publications, Conference presentation, Research and Development Report, Patent, etc.) of the members of National Institutes for Quantum Science and Technology.
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Inosine nucleotides, including ribo- and deoxyinosine nucleotides, are generated as products of oxidative deamination of adenine nucleotides as well as a precursor for purine nucleotide biosynthesis in living cells. These inosine nucleotides are converted to corresponding triphosphate forms by phosphorylation and can be incorporated into DNA or RNA. We have identified ITPA and NUDT16 as inosine nucleotides hydrolyzing enzymes in mammalian cells, and reported that ITPA deficiency results in perinatal lethality in mice with accumulation of inosine nucleotides, and that deficiency of either ITPA or NUDT16 causes growth arrest and genome instability in cultured mouse or human cells. To elucidate mechanisms of the cellular dysfunctions caused by deficiencies of ITPA or NUDT16 in human cells, we examined effects of simultaneous knockdown of several DNA repair enzymes in addition to ITPA or NUDT16, and found that knockdown of only one of mismatch repair genes suppresses the dysfunctions. Knockdown of ITPA or NUDT16 in mismatch repair deficient and proficient cells confirmed the results. We also found that simultaneous knockdown of two DNA excision repair enzymes exacerbated the dysfunctions, indicating that deoxyinosine incorporated into DNA causes the dysfunctions. The present study indicates that endogenous deoxyinosine nucleotides cause mismatch repair-dependent cell growth arrest and genome instability in human cells if they are not excluded from the nucleotide pool.
ほ乳動物細胞におけるデオキシイノシンヌクレオチドによるゲノム不安定化機構とその防御システム
