Journal
NUCLEIC ACIDS RESEARCH
Volume 40, Issue 15, Pages 7368-7374Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gks357
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Funding
- National Institutes of Health [R01 CA101864, R01 ES016114, R01 DK071111, R01 DK088561, P30 DK41296]
- NIH [R01 CA101864]
- [P30CA047904]
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Exposure to reactive oxygen species (ROS) can give rise to the formation of various DNA damage products. Among them, d(G[8-5m]T) can be induced in isolated DNA treated with Fenton reagents and in cultured human cells exposed to gamma-rays, d(G[8-5m]T) can be recognized and incised by purified Escherichia coli UvrABC nuclease. However, it remains unexplored whether d(G[8-5 m]T) accumulates in mammalian tissues and whether it is a substrate for nucleotide excision repair (NER) in vivo. Here, we found that d(G[8-5 m]T) could be detected in DNA isolated from tissues of healthy humans and animals, and elevated endogenous ROS generation enhanced the accumulation of this lesion in tissues of a rat model of Wilson's disease. Additionally, XPA-deficient human brain and mouse liver as well as various types of tissues of ERCC1-deficient mice contained higher levels of d(G[8-5 m]T) but not ROS-induced single-nucleobase lesions than the corresponding normal controls. Together, our studies established that d(G[8-5 m]T) can be induced endogenously in mammalian tissues and constitutes a substrate for NER in vivo.
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