DNA abasic lesions in a different light: solution structure of an endogenous topoisomerase II poison.
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.
Cline
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Department of Biochemistry, Vanderbilt University School of Medicine, Nashville Tennessee 37232-0146, USA.
Jones
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Stone
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Osheroff
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D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism; D001080:Apurinic Acid / Q000737:chemistry* / Q000378:metabolism; D001483:Base Sequence / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000737:chemistry* / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000737:chemistry* / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics; D003855:Deoxyribose / Q000737:chemistry; D005663:Furans / Q000737:chemistry; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry* / Q000378:metabolism; D007527:Isoenzymes / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D051788:Myeloid-Lymphoid Leukemia Protein; D019906:Nuclear Magnetic Resonance, Biomolecular; D009690:Nucleic Acid Conformation / Q000187:drug effects; D011519:Proto-Oncogenes; D012996:Solutions; D014157:Transcription Factors
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D005663:Furans; D007364:Intercalating Agents; D007527:Isoenzymes; C497422:KMT2A protein, human; D012996:Solutions; D014157:Transcription Factors; D001080:Apurinic Acid; D051788:Myeloid-Lymphoid Leukemia Protein; C018674:tetrahydrofuran; D003855:Deoxyribose; D011495:Histone-Lysine N-Methyltransferase; D004250:DNA Topoisomerases, Type II