Induction of OGG1 gene expression by HIV-1 Tat.
To identify the cellular gene target for Tat, we performed gene expression profile analysis and found that Tat up-regulates the expression of the OGG1 (8-oxoguanine-DNA glycosylase-1) gene, which encodes an enzyme responsible for repairing the oxidatively damaged guanosine, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG). We observed that Tat induced OGG1 gene expression by enhancing its promoter activity without changing its mRNA stability. We found that the upstream AP-4 site within the OGG1 promoter is responsible and that Tat interacted with AP-4 and removed AP-4 from the OGG1 promoter by in vivo chromatin immunoprecipitation assay. Thus, Tat appears to activate OGG1 expression by sequestrating AP-4. Interestingly, although Tat induces oxidative stress known to generate 8-oxo-dG, which causes the G:C to T:A transversion, we observed that the amount of 8-oxo-dG was reduced by Tat. When OGG1 was knocked down by small interfering RNA, Tat increased the amount of 8-oxo-dG, thus confirming the role of OGG1 in preventing the formation of 8-oxo-dG. These findings collectively indicate the possibility that Tat may play a role in maintenance of the genetic integrity of the proviral and host cellular genomes by up-regulating OGG1 as a feed-forward mechanism.
Imai
Kenichi
K
Department of Molecular and Cellular Biology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601.
Nakata
Kenji
K
Kawai
Kazuaki
K
Hamano
Takaichi
T
Mei
Nan
N
Kasai
Hiroshi
H
Okamoto
Takashi
T
D001665:Binding Sites; D002460:Cell Line; D045647:DNA Glycosylases / Q000235:genetics* / Q000502:physiology; D004268:DNA-Binding Proteins; D003839:Deoxyadenosines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D015696:Gene Products, tat / Q000494:pharmacology*; D006801:Humans; D011401:Promoter Regions, Genetic / Q000187:drug effects; D020871:RNA Stability; D014157:Transcription Factors; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics
D004268:DNA-Binding Proteins; D003839:Deoxyadenosines; D015696:Gene Products, tat; D014157:Transcription Factors; C055473:enhancer-binding protein AP-4; C078251:2'-deoxy-7,8-dihydro-8-oxoadenosine; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human