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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Exocyclic DNA lesions stimulate DNA cleavage mediated by human topoisomerase II alpha in vitro and in cultured cells.

Authors: Vélez-Cruz, Renier; Riggins, James N; Daniels, J Scott; Cai, Hongliang; Guengerich, F Peter; Marnett, Lawrence J; Osheroff, Neil

Published In Biochemistry, (2005 Mar 15)

Abstract: DNA adducts are mutagenic and clastogenic. Because of their harmful nature, lesions are recognized by many proteins involved in DNA repair. However, mounting evidence suggests that lesions also are recognized by proteins with no obvious role in repair processes. One such protein is topoisomerase II, an essential enzyme that removes knots and tangles from the DNA. Because topoisomerase II generates a protein-linked double-stranded DNA break during its catalytic cycle, it has the potential to fragment the genome. Previous studies indicate that abasic sites and other lesions that distort the double helix stimulate topoisomerase II-mediated DNA cleavage. Therefore, to further explore interactions between DNA lesions and the enzyme, the effects of exocyclic adducts on DNA cleavage mediated by human topoisomerase IIalpha were determined. When located within the four-base overhang of a topoisomerase II cleavage site (at the +2 or +3 position 3' relative to the scissile bond), 3,N(4)-ethenodeoxycytidine, 3,N(4)-etheno-2'-ribocytidine, 1,N(2)-ethenodeoxyguanosine, pyrimido[1,2-a]purin-10(3H)-one deoxyribose (M(1)dG), and 1,N(2)-propanodeoxyguanosine increased DNA scission approximately 5-17-fold. Enhanced cleavage did not result from an increased affinity of topoisomerase IIalpha for adducted DNA or a decreased rate of religation. Therefore, it is concluded that these exocyclic lesions act by accelerating the forward rate of enzyme-mediated DNA scission. Finally, treatment of cultured human cells with 2-chloroacetaldehyde, a reactive metabolite of vinyl chloride that generates etheno adducts, increased cellular levels of DNA cleavage by topoisomerase IIalpha. This finding suggests that type II topoisomerases interact with exocyclic DNA lesions in physiological systems.

PubMed ID: 15751973 Exiting the NIEHS site

MeSH Terms: Acetaldehyde/analogs & derivatives*; Acetaldehyde/metabolism; Acetaldehyde/toxicity; Alkylating Agents/metabolism; Alkylating Agents/toxicity; Antigens, Neoplasm/chemistry*; Antigens, Neoplasm/metabolism; Cell Line, Tumor; Cell Survival/drug effects; Cell Survival/genetics; Cell Survival/physiology; DNA Adducts/metabolism; DNA Adducts/toxicity*; DNA Damage*/drug effects; DNA Damage*/genetics; DNA Damage*/physiology; DNA Repair/genetics; DNA Repair/physiology; DNA Topoisomerases, Type II/chemistry*; DNA Topoisomerases, Type II/metabolism; DNA-Binding Proteins/chemistry*; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Deoxyguanosine/analogs & derivatives*; Deoxyguanosine/metabolism; Deoxyguanosine/toxicity; Histone-Lysine N-Methyltransferase; Humans; Myeloid-Lymphoid Leukemia Protein; Proto-Oncogenes/genetics; Transcription Factors/chemistry; Transcription Factors/genetics

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