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Nucleic Acids Research Advance Access originally published online on December 15, 2007
Nucleic Acids Research 2008 36(3):742-755; doi:10.1093/nar/gkm1092
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Nucleic Acids Research, 2008, Vol. 36, No. 3 742-755
© 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.

Chemistry

Oxidation of single-stranded oligonucleotides by carbonate radical anions: generating intrastrand cross-links between guanine and thymine bases separated by cytosines

Conor Crean, Yuriy Uvaydov, Nicholas E. Geacintov and Vladimir Shafirovich*

Chemistry Department and Radiation and Solid State Laboratory, 31 Washington Place, New York University, New York, NY 10003-5180, USA

*To whom correspondence should be addressed. Tel: +1 212 998 8456; Fax: +1 212 998 8421; Email: vs5{at}nyu.edu

Received November 1, 2007. Revised November 21, 2007. Accepted November 21, 2007.

The carbonate radical anion is a biologically important one-electron oxidant that can directly abstract an electron from guanine, the most easily oxidizable DNA base. Oxidation of the 5'-d(CCTACGCTACC) sequence by photochemically generated CO3·– radicals in low steady-state concentrations relevant to biological processes results in the formation of spiroiminodihydantoin diastereomers and a previously unknown lesion. The latter was excised from the oxidized oligonucleotides by enzymatic digestion with nuclease P1 and alkaline phosphatase and identified by LC-MS/MS as an unusual intrastrand cross-link between guanine and thymine. In order to further characterize the structure of this lesion, 5'-d(GpCpT) was exposed to CO3·– radicals, and the cyclic nature of the 5'-d(G*pCpT*) cross-link in which the guanine C8-atom is bound to the thymine N3-atom was confirmed by LC-MS/MS, 1D and 2D NMR studies. The effect of bridging C bases on the cross-link formation was studied in the series of 5'-d(GpCnpT) and 5'-d(TpCnpG) sequences with n = 0, 1, 2 and 3. Formation of the G*-T* cross-links is most efficient in the case of 5'-d(GpCpT). Cross-link formation (n = 0) was also observed in double-stranded DNA molecules derived from the self-complementary 5'-d(TTACGTACGTAA) sequence following exposure to CO3·– radicals and enzymatic excision of the 5'-d(G*pT*) product.


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