title: Selective binding of tumor suppressor p53 protein to topologically constrained DNA: Modulation by intercalative drugs.
abstract: Selective binding of the wild type tumor suppressor protein p53 to negatively and positively supercoiled (sc) DNA was studied using intercalative drugs chloroquine (CQ), ethidium bromide, acridine derivatives and doxorubicin as a modulators of the level of DNA supercoiling. The p53 was found to lose gradually its preferential binding to negatively scDNA with increasing concentrations of intercalators until the DNA negative superhelix turns were relaxed. Formation of positive superhelices (due to further increasing intercalator concentrations) rendered the circular duplex DNA to be preferentially bound by the p53 again. CQ at concentrations modulating the closed circular DNA topology did not prevent the p53 from recognizing a specific target sequence within topologically unconstrained linear DNA. Experiments with DNA topoisomer distributions differing in their superhelix densities revealed the p53 to bind selectively DNA molecules possessing higher number of negative or positive superturns. Possible modes of the p53 binding to the negatively or positively supercoiled DNA and tentative biological consequences are discussed.
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Královopolská 135, 612 65 Brno, Czech Republic. hapi@ibp.cz
authors.forename: Hana
authors.initials: H
authors.lastname: Pivonková
authors.forename: Peter
authors.initials: P
authors.lastname: Sebest
authors.forename: Petr
authors.initials: P
authors.lastname: Pecinka
authors.forename: Olga
authors.initials: O
authors.lastname: Tichá
authors.forename: Katerina
authors.initials: K
authors.lastname: Nemcová
authors.forename: Marie
authors.initials: M
authors.lastname: Brázdová
authors.forename: Eva Brázdová
authors.initials: EB
authors.lastname: Jagelská
authors.forename: Václav
authors.initials: V
authors.lastname: Brázda
authors.forename: Miroslav
authors.initials: M
authors.lastname: Fojta
mesh_terms: D000166:Acridines / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D002738:Chloroquine / Q000737:chemistry / Q000494:pharmacology; D004278:DNA, Superhelical / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology; D009690:Nucleic Acid Conformation / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000166:Acridines; D004278:DNA, Superhelical; D007364:Intercalating Agents; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D002738:Chloroquine