Endogenous formation and repair of oxidatively induced G[8-5 m]T intrastrand cross-link lesion |
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Authors: | Wang Jin Cao Huachuan You Changjun Yuan Bifeng Bahde Ralf Gupta Sanjeev Nishigori Chikako Niedernhofer Laura J Brooks Philip J Wang Yinsheng |
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Institution: | Department of Chemistry, University of California, Riverside, CA 92521-0403, Department of Medicine, Department of Pathology, Marion Bessin Liver Research Center, Diabetes Center, Cancer Center, Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Institute for Clinical and Translational Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA, Division of Dermatology, Graduate School of Medicine, Kobe University, Kobe 650-0017, Japan, Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 523 Bridgeside Point II, 450 Technology Drive, Pittsburgh, PA 15219 and Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD 20852, USA. |
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Abstract: | Exposure to reactive oxygen species (ROS) can give rise to the formation of various DNA damage products. Among them, d(G8-5 m]T) can be induced in isolated DNA treated with Fenton reagents and in cultured human cells exposed to γ-rays, d(G8-5m]T) can be recognized and incised by purified Escherichia coli UvrABC nuclease. However, it remains unexplored whether d(G8-5 m]T) accumulates in mammalian tissues and whether it is a substrate for nucleotide excision repair (NER) in vivo. Here, we found that d(G8-5 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(G8-5 m]T) but not ROS-induced single-nucleobase lesions than the corresponding normal controls. Together, our studies established that d(G8-5 m]T) can be induced endogenously in mammalian tissues and constitutes a substrate for NER in vivo. |
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