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Proc Natl Acad Sci U S A. 2018 Apr 17;115(16):4218-4222. doi: 10.1073/pnas.1718363115. Epub 2018 Apr 2.

Transcriptional mutagenesis mediated by 8-oxoG induces translational errors in mammalian cells.

Author information

1
MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, 100730 Beijing, People's Republic of China.
2
Frontier Research Center, Fukuoka Dental College, 8140193 Fukuoka, Japan.
3
Beijing Genomics Institute-Shenzhen, 518083 Shenzhen, People's Republic of China.
4
Department of Pharmacology, Wenzhou Medical College, Wenzhou, 325035 Zhejiang, People's Republic of China.
5
Cancer Institute and Hospital, Chinese Academy of Medical Sciences, 100021 Beijing, People's Republic of China.
6
Thermo Fisher Scientific Demonstration Laboratory, 201206 Shanghai, People's Republic of China.
7
Peking University Fifth School of Clinical Medicine, Beijing Hospital, 100730 Beijing, People's Republic of China.
8
Department of Cardiology, Beijing Hospital, 100730 Beijing, People's Republic of China.
9
Department of Pathology, Beijing Hospital, 100730 Beijing, People's Republic of China.
10
Department of Neurology, Beijing Hospital, 100730 Beijing, People's Republic of China.
11
Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, 100021 Beijing, People's Republic of China.
12
Beijing Red Cross Blood Center, 100088 Beijing, People's Republic of China.
13
James D. Watson Institute of Genome Sciences, 310058 Hangzhou, People's Republic of China.
14
Genome Integrity and Structural Biology Laboratory, National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
15
Frontier Research Center, Fukuoka Dental College, 8140193 Fukuoka, Japan; caijp61@vip.sina.com mseki@college.fdcnet.ac.jp.
16
MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, 100730 Beijing, People's Republic of China; caijp61@vip.sina.com mseki@college.fdcnet.ac.jp.

Abstract

Reactive oxygen species formed within the mammalian cell can produce 8-oxo-7,8-dihydroguanine (8-oxoG) in mRNA, which can cause base mispairing during gene expression. Here we found that administration of 8-oxoGTP in MTH1-knockdown cells results in increased 8-oxoG content in mRNA. Under this condition, an amber mutation of the reporter luciferase is suppressed. Using second-generation sequencing techniques, we found that U-to-G changes at preassigned sites of the luciferase transcript increased when 8-oxoGTP was supplied. In addition, an increased level of 8-oxoG content in RNA induced the accumulation of aggregable amyloid β peptides in cells expressing amyloid precursor protein. Our findings indicate that 8-oxoG accumulation in mRNA can alter protein synthesis in mammalian cells. Further work is required to assess the significance of these findings under normal physiological conditions.

KEYWORDS:

8-oxoG; MTH1; RNA oxidization; amyloid β peptides

PMID:
29610342
PMCID:
PMC5910836
DOI:
10.1073/pnas.1718363115
[Indexed for MEDLINE]
Free PMC Article

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