Deoxyribose oxidation chemistry and endogenous DNA adducts

Endogenous and exogenous oxidants react with cellular macromolecules to generate a variety of electrophiles that react with DNA produce cytotoxic and mutagenic adducts. One source of such electrophiles is deoxyribose in DNA itself. Oxidation of each position in deoxyribose generates a unique spectrum of products, many of which are highly reactive with DNA bases and lead to formation of adducts. The objective of this thesis was to clarify the chemistry of deoxyribose oxidation, with a focus on C4'-oxidation that gives rise to 3'- phosphoglycolate residues on the DNA backbone and releases base propenal or malondialdehyde, and to investigate the role of base propenals in the formation of an important endogenous DNA adduct, MI dG. First, an index of total deoxyribose oxidation was developed, one that provides a means to compare different oxidizing agents. This method exploits the reaction of aldehyde- and ketone-containing deoxyribose oxidation products with 14C-methoxyamine to form stable oxime derivatives that are quantified by accelerator mass spectrometry. Sensitive GC/MS methods were developed to quantify 3'-phosphoglycolate residues from deoxyribose C4'-oxidation and HPLC/post-column derivatization methods were developed to quantify the corresponding base propenal or malondialdehyde.

Department dc:contributor.department

Massachusetts Institute of Technology. Biological Engineering Division.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2006

Author dc:creator

• Zhou, Xinfeng

Advisor dc:contributor.advisor

• Peter C. Dedon.

• Biological Engineering Division.

Statement dc:rights

• MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/37954

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/37954