TY - JOUR
T1 - Biochemical evaluation of genotoxic biomarkers for 2-deoxyribonolactone- mediated cross-link formation with histones
AU - Son, Mi Young
AU - Jun, Hyun Ik
AU - Lee, Kwang Geun
AU - Demple, Bruce
AU - Sung, Jung Suk
PY - 2009/1
Y1 - 2009/1
N2 - Numerous environmental carcinogens involve radical formation interacting with DNA to produce 2-deoxyribonolactone (dL), a major type of oxidized abasic site, implicated in DNA strand breaks, mutagenesis, and formation of covalent DNA-protein cross-links (DPC). Studies showed major dL-specific DPC occurred due to reactions with DNA polymerase (Pol) dependent on native conformation, while other DPC formed involved nonenzymatic reactions of DNA binding proteins with dL lesions. Pol appeared to play a major role in alleviating the cytotoxic effects of neocarzinostatin, which was used as a dL-producing agent. When a duplex DNA containing a dL at a site-specific position was incubated with purified histones, DPC were formed between dL and each histone protein, including H1, H2A, H2B, H3, and H4. Comparative kinetic analysis of DPC formation with histones and Pol revealed two distinct mechanisms of dL-mediated DPC formation. The rate of DPC formation with Pol was approximately two orders of magnitude higher than that with various histone proteins. These results indicate that catalytic activity of Pol mediates rapid DPC formation between dL and this DNA repair enzyme, whereas nonenzymatic reactions of dL with histones form DPC more slowly. The abundance of histones and their constant interaction with DNA may nevertheless yield significant levels of DPC with dL, as biomarkers of dL-induced cytotoxicity. Overall, data suggest that occurrence of dL-mediated DPC with histones may contribute to the genotoxic effects of dL in DNA.
AB - Numerous environmental carcinogens involve radical formation interacting with DNA to produce 2-deoxyribonolactone (dL), a major type of oxidized abasic site, implicated in DNA strand breaks, mutagenesis, and formation of covalent DNA-protein cross-links (DPC). Studies showed major dL-specific DPC occurred due to reactions with DNA polymerase (Pol) dependent on native conformation, while other DPC formed involved nonenzymatic reactions of DNA binding proteins with dL lesions. Pol appeared to play a major role in alleviating the cytotoxic effects of neocarzinostatin, which was used as a dL-producing agent. When a duplex DNA containing a dL at a site-specific position was incubated with purified histones, DPC were formed between dL and each histone protein, including H1, H2A, H2B, H3, and H4. Comparative kinetic analysis of DPC formation with histones and Pol revealed two distinct mechanisms of dL-mediated DPC formation. The rate of DPC formation with Pol was approximately two orders of magnitude higher than that with various histone proteins. These results indicate that catalytic activity of Pol mediates rapid DPC formation between dL and this DNA repair enzyme, whereas nonenzymatic reactions of dL with histones form DPC more slowly. The abundance of histones and their constant interaction with DNA may nevertheless yield significant levels of DPC with dL, as biomarkers of dL-induced cytotoxicity. Overall, data suggest that occurrence of dL-mediated DPC with histones may contribute to the genotoxic effects of dL in DNA.
UR - http://www.scopus.com/inward/record.url?scp=75749122713&partnerID=8YFLogxK
U2 - 10.1080/15287390903212402
DO - 10.1080/15287390903212402
M3 - Article
C2 - 20077202
AN - SCOPUS:75749122713
SN - 1528-7394
VL - 72
SP - 1311
EP - 1317
JO - Journal of Toxicology and Environmental Health - Part A: Current Issues
JF - Journal of Toxicology and Environmental Health - Part A: Current Issues
IS - 21-22
ER -