Catalytic inhibition of DNA topoisomerase IIalpha by sodium azide.
It has been demonstrated previously that sodium azide reduces the clastogenicity of several DNA topoisomerase II (topo II) poisons in cultured mammalian cells. These studies suggested that azide may be a catalytic topo II inhibitor. Azide interferes with mitochondrial production of ATP and is also known to inhibit cellular ATPases. Since topo II requires ATP for catalytic activity (enzyme turnover), it seemed likely that interference with ATP levels or ATP catabolism was the underlying mechanism of topo II inactivation; however, this has not been examined in living cells under conditions where the endogenous topo II is active on genomic DNA. The present studies were carried out to verify that azide inhibits endogenous topo II in cells. We show that azide blocks both decatenation and relaxation activity of purified topo II in a concentration dependent manner and reduces topoII/DNA covalent complex formation in cells. From these studies, it is concluded that sodium azide catalytically inactivates topo II via an ATP-sensitive process.
Ju
R
R
Department of Molecular Genetics, Ohio State University, Columbus, OH 43210, USA.
Mao
Y
Y
Glick
M J
MJ
Muller
M T
MT
Snyder
R D
RD
D000951:Antigens, Neoplasm; D000972:Antineoplastic Agents, Phytogenic; D002384:Catalysis / Q000187:drug effects; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D005047:Etoposide; D006367:HeLa Cells; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000737:chemistry; D019810:Sodium Azide / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors
D000951:Antigens, Neoplasm; D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D019810:Sodium Azide; D004250:DNA Topoisomerases, Type II