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Nucleic Acids Research Advance Access published online on October 16, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm851
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Genomics

Formation and genotoxicity of a guanine–cytosine intrastrand cross-link lesion in vivo

Haizheng Hong1, Huachuan Cao2 and Yinsheng Wang1,2,*

1Environmental Toxicology Graduate Program and 2Department of Chemistry, University of California, Riverside, CA 92521-0403, USA

* To whom correspondence should be addressed. Tel: +1 951 827 2700; Fax: +1 951 827 4713; Email: yinsheng.wang{at}ucr.edu.

Received August 10, 2007. Revised September 24, 2007. Accepted September 26, 2007.

Reactive oxygen species (ROS) can be induced by both endogenous and exogenous processes, and they can damage biological molecules including nucleic acids. Exposure of isolated DNA to X/{gamma}-rays and Fenton reagents was shown to lead to the formation of intrastrand cross-link lesions where the neighboring nucleobases in the same DNA strand are covalently bonded. By employing HPLC coupled with tandem mass spectrometry (LC-MS/MS) with the isotope dilution method, we assessed quantitatively the formation of a guanine–cytosine (G[8-5]C) intrastrand cross-link lesion in HeLa-S3 cells upon exposure to {gamma}-rays. The yield of the G[8-5]C cross-link was 0.037 lesions per 109 nucleosides per Gy, which was ~300 times lower than that of 5-formyl-2'-deoxyuridine (0.011 lesions per 106 nucleosides per Gy) under identical exposure conditions. We further constructed a single-stranded M13 genome harboring a site-specifically incorporated G[8-5]C lesion and developed a novel mass spectrometry-based method for interrogating the products emanating from the replication of the genome in Escherichia coli cells. The results demonstrated that G[8-5]C blocked considerably DNA replication as represented by a 20% bypass efficiency, and the lesion was significantly mutagenic in vivo, which included a 8.7% G->T and a 1.2% G->C transversion mutations. DNA replication in E. coli hosts deficient in SOS-induced polymerases revealed that polymerase V was responsible for the error-prone translesion synthesis in vivo.


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