DNA abasic lesions in a different light: solution structure of an endogenous topoisomerase II poison.

Cline SD, Jones WR, Stone MP, Osheroff N
Biochemistry. 1999 38 (47): 15500-7

PMID: 10569932 · DOI:10.1021/bi991750s

Topoisomerase II is the target for several anticancer drugs that "poison" the enzyme and convert it to a cellular toxin by increasing topoisomerase II-mediated DNA cleavage. In addition to these "exogenous topoisomerase II poisons," DNA lesions such as abasic sites act as "endogenous poisons" of the enzyme. Drugs and lesions are believed to stimulate DNA scission by altering the structure of the double helix within the cleavage site of the enzyme. However, the structural alterations that enhance cleavage are unknown. Since abasic sites are an intrinsic part of the genetic material, they represent an attractive model to assess DNA distortions that lead to altered topoisomerase II function. Therefore, the structure of a double-stranded dodecamer containing a tetrahydrofuran apurinic lesion at the +2 position of a topoisomerase II DNA cleavage site was determined by NMR spectroscopy. Three major features distinguished the apurinic structure ( = 0.095) from that of wild-type ( = 0.077). First, loss of base stacking at the lesion collapsed the major groove and reduced the distance between the two scissile phosphodiester bonds. Second, the apurinic lesion induced a bend that was centered about the topoisomerase II cleavage site. Third, the base immediately opposite the lesion was extrahelical and relocated to the minor groove. All of these structural alterations have the potential to influence interactions between topoisomerase II and its DNA substrate.

MeSH Terms (20)

Antigens, Neoplasm Antineoplastic Agents Apurinic Acid Base Sequence Deoxyribose DNA, Neoplasm DNA-Binding Proteins DNA Topoisomerases, Type II Furans Histone-Lysine N-Methyltransferase Humans Intercalating Agents Isoenzymes Models, Molecular Myeloid-Lymphoid Leukemia Protein Nuclear Magnetic Resonance, Biomolecular Nucleic Acid Conformation Proto-Oncogenes Solutions Transcription Factors

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