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Human topoisomerase IIalpha uses a two-metal-ion mechanism for DNA cleavage.
Deweese, Joseph E; Burgin, Alex B; Osheroff, Neil.
Afiliação
  • Deweese JE; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA.
Nucleic Acids Res ; 36(15): 4883-93, 2008 Sep.
Article em En | MEDLINE | ID: mdl-18653531
ABSTRACT
The DNA cleavage reaction of human topoisomerase IIalpha is critical to all of the physiological and pharmacological functions of the protein. While it has long been known that the type II enzyme requires a divalent metal ion in order to cleave DNA, the role of the cation in this process is not known. To resolve this fundamental issue, the present study utilized a series of divalent metal ions with varying thiophilicities in conjunction with DNA cleavage substrates that replaced the 3'-bridging oxygen of the scissile bond with a sulfur atom (i.e. 3'-bridging phosphorothiolates). Rates and levels of DNA scission were greatly enhanced when thiophilic metal ions were included in reactions that utilized sulfur-containing substrates. Based on these results and those of reactions that employed divalent cation mixtures, we propose that topoisomerase IIalpha mediates DNA cleavage via a two-metal-ion mechanism. In this model, one of the metal ions makes a critical interaction with the 3'-bridging atom of the scissile phosphate. This interaction greatly accelerates rates of enzyme-mediated DNA cleavage, and most likely is needed to stabilize the leaving 3'-oxygen.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: DNA Topoisomerases Tipo II / Proteínas de Ligação a DNA / Clivagem do DNA / Metais / Modelos Químicos / Antígenos de Neoplasias Limite: Humans Idioma: En Ano de publicação: 2008 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: DNA Topoisomerases Tipo II / Proteínas de Ligação a DNA / Clivagem do DNA / Metais / Modelos Químicos / Antígenos de Neoplasias Limite: Humans Idioma: En Ano de publicação: 2008 Tipo de documento: Article