In Situ Analysis of 8-Oxo-7,8-dihydro-2′-deoxyguanosine Oxidation Reveals Sequence- and Agent-Specific Damage Spectra
Guanine is a major target for oxidation in DNA, with 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) as a major product. 8-oxodG is itself significantly more susceptible to oxidation than guanine, with the resulting damage consisting of more than 10 different products. This complexity has hampered eff...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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American Chemical Society (ACS)
2014
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| Online Access: | http://hdl.handle.net/1721.1/88781 https://orcid.org/0000-0003-0011-3067 https://orcid.org/0000-0001-8533-2706 https://orcid.org/0000-0002-2325-552X https://orcid.org/0000-0002-4607-5337 |
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| author | Lim, Kok Seong Cui, Liang Taghizadeh, Koli Wishnok, John S. Chan, Wan Simon DeMott, Michael S. Babu, I. Ramesh Dedon, Peter C. Tannenbaum, Steven Robert |
| author2 | Massachusetts Institute of Technology. Center for Environmental Health Sciences |
| author_facet | Massachusetts Institute of Technology. Center for Environmental Health Sciences Lim, Kok Seong Cui, Liang Taghizadeh, Koli Wishnok, John S. Chan, Wan Simon DeMott, Michael S. Babu, I. Ramesh Dedon, Peter C. Tannenbaum, Steven Robert |
| author_sort | Lim, Kok Seong |
| collection | MIT |
| description | Guanine is a major target for oxidation in DNA, with 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) as a major product. 8-oxodG is itself significantly more susceptible to oxidation than guanine, with the resulting damage consisting of more than 10 different products. This complexity has hampered efforts to understand the determinants of biologically relevant DNA oxidation chemistry. To address this problem, we have developed a high mass accuracy mass spectrometric method to quantify oxidation products arising site specifically in DNA. We applied this method to quantify the role of sequence context in defining the spectrum of damage products arising from oxidation of 8-oxodG by two oxidants: nitrosoperoxycarbonate (ONOOCO[subscript 2]–), a macrophage-derived chemical mediator of inflammation, and the classical one-electron oxidant, riboflavin-mediated photooxidation. The results reveal the predominance of dehydroguanidinohydantoin (DGh) in 8-oxodG oxidation by both oxidants. While the relative quantities of 8-oxodG oxidation products arising from ONOOCO[subscript 2]– did not vary as a function of sequence context, products of riboflavin-mediated photooxidation of 8-oxodG were highly sequence dependent. Several of the 8-oxodG oxidation products underwent hydrolytic conversion to new products with half-lives of 2–7 h. The results have implications for understanding the chemistry of DNA oxidation and the biological response to the damage, with DNA damage recognition and repair systems faced with a complex and dynamic set of damage targets. |
| first_indexed | 2024-09-23T11:42:05Z |
| format | Article |
| id | mit-1721.1/88781 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:42:05Z |
| publishDate | 2014 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/887812022-10-01T05:22:37Z In Situ Analysis of 8-Oxo-7,8-dihydro-2′-deoxyguanosine Oxidation Reveals Sequence- and Agent-Specific Damage Spectra Lim, Kok Seong Cui, Liang Taghizadeh, Koli Wishnok, John S. Chan, Wan Simon DeMott, Michael S. Babu, I. Ramesh Dedon, Peter C. Tannenbaum, Steven Robert Massachusetts Institute of Technology. Center for Environmental Health Sciences Massachusetts Institute of Technology. Department of Biological Engineering Lim, Kok Seong Cui, Liang Taghizadeh, Koli Wishnok, John S. Chan, Wan Simon DeMott, Michael S. Babu, I. Ramesh Tannenbaum, Steven Robert Dedon, Peter C. Guanine is a major target for oxidation in DNA, with 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) as a major product. 8-oxodG is itself significantly more susceptible to oxidation than guanine, with the resulting damage consisting of more than 10 different products. This complexity has hampered efforts to understand the determinants of biologically relevant DNA oxidation chemistry. To address this problem, we have developed a high mass accuracy mass spectrometric method to quantify oxidation products arising site specifically in DNA. We applied this method to quantify the role of sequence context in defining the spectrum of damage products arising from oxidation of 8-oxodG by two oxidants: nitrosoperoxycarbonate (ONOOCO[subscript 2]–), a macrophage-derived chemical mediator of inflammation, and the classical one-electron oxidant, riboflavin-mediated photooxidation. The results reveal the predominance of dehydroguanidinohydantoin (DGh) in 8-oxodG oxidation by both oxidants. While the relative quantities of 8-oxodG oxidation products arising from ONOOCO[subscript 2]– did not vary as a function of sequence context, products of riboflavin-mediated photooxidation of 8-oxodG were highly sequence dependent. Several of the 8-oxodG oxidation products underwent hydrolytic conversion to new products with half-lives of 2–7 h. The results have implications for understanding the chemistry of DNA oxidation and the biological response to the damage, with DNA damage recognition and repair systems faced with a complex and dynamic set of damage targets. National Cancer Institute (U.S.) (Grant CA026731) National Cancer Institute (U.S.) (Grant CA110261) 2014-08-18T18:40:41Z 2014-08-18T18:40:41Z 2012-10 2012-07 Article http://purl.org/eprint/type/JournalArticle 0002-7863 1520-5126 http://hdl.handle.net/1721.1/88781 Lim, Kok Seong, Liang Cui, Koli Taghizadeh, John S. Wishnok, Wan Chan, Michael S. DeMott, I. Ramesh Babu, Steven R. Tannenbaum, and Peter C. Dedon. “In Situ Analysis of 8-Oxo-7,8-Dihydro-2′-Deoxyguanosine Oxidation Reveals Sequence- and Agent-Specific Damage Spectra.” Journal of the American Chemical Society 134, no. 43 (October 31, 2012): 18053–18064. https://orcid.org/0000-0003-0011-3067 https://orcid.org/0000-0001-8533-2706 https://orcid.org/0000-0002-2325-552X https://orcid.org/0000-0002-4607-5337 en_US http://dx.doi.org/10.1021/ja307525h Journal of the American Chemical Society Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society (ACS) PMC |
| spellingShingle | Lim, Kok Seong Cui, Liang Taghizadeh, Koli Wishnok, John S. Chan, Wan Simon DeMott, Michael S. Babu, I. Ramesh Dedon, Peter C. Tannenbaum, Steven Robert In Situ Analysis of 8-Oxo-7,8-dihydro-2′-deoxyguanosine Oxidation Reveals Sequence- and Agent-Specific Damage Spectra |
| title | In Situ Analysis of 8-Oxo-7,8-dihydro-2′-deoxyguanosine Oxidation Reveals Sequence- and Agent-Specific Damage Spectra |
| title_full | In Situ Analysis of 8-Oxo-7,8-dihydro-2′-deoxyguanosine Oxidation Reveals Sequence- and Agent-Specific Damage Spectra |
| title_fullStr | In Situ Analysis of 8-Oxo-7,8-dihydro-2′-deoxyguanosine Oxidation Reveals Sequence- and Agent-Specific Damage Spectra |
| title_full_unstemmed | In Situ Analysis of 8-Oxo-7,8-dihydro-2′-deoxyguanosine Oxidation Reveals Sequence- and Agent-Specific Damage Spectra |
| title_short | In Situ Analysis of 8-Oxo-7,8-dihydro-2′-deoxyguanosine Oxidation Reveals Sequence- and Agent-Specific Damage Spectra |
| title_sort | in situ analysis of 8 oxo 7 8 dihydro 2 deoxyguanosine oxidation reveals sequence and agent specific damage spectra |
| url | http://hdl.handle.net/1721.1/88781 https://orcid.org/0000-0003-0011-3067 https://orcid.org/0000-0001-8533-2706 https://orcid.org/0000-0002-2325-552X https://orcid.org/0000-0002-4607-5337 |
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