2',5'-oligoadenylates inhibit relaxation of supercoiled DNA by calf thymus DNA topoisomerase I.
DNA topoisomerases interconvert various topological isomers of DNA and play key roles in replication and gene expression. The possible involvement of the 2',5'-oligoadenylates (2-5A) system in cell growth, regulation, and cell differentiation led us to investigate the effects of 2-5A on mammalian topoisomerases. We found that the calf thymus type I topoisomerase was inhibited by a variety of 2-5A compounds. The level of inhibition was dependent upon the number of residues and the degree of phosphorylation at the 5' terminus. The 5'-triphosphorylated 2',5' hexamer, ppp(Ap)5A, was the most effective, strongly reducing relaxation at less than micromolar concentrations. These results raise the possibility that physiological concentrations of 2-5A of sufficient chain length may be capable of regulating gene expression by virtue of a direct inhibition of DNA topoisomerase I.
Castora
F J
FJ
Department of Biochemistry, Eastern Virginia Medical School, Norfolk 23501.
Erickson
C E
CE
Kovács
T
T
Lesiak
K
K
Torrence
P F
PF
D000227:Adenine Nucleotides / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002417:Cattle; D004278:DNA, Superhelical / Q000187:drug effects*; D004587:Electrophoresis, Agar Gel; D005786:Gene Expression Regulation / Q000187:drug effects; D007700:Kinetics; D009841:Oligonucleotides / Q000494:pharmacology; D009843:Oligoribonucleotides / Q000138:chemical synthesis / Q000494:pharmacology*; D010766:Phosphorylation; D013950:Thymus Gland / Q000201:enzymology*; D059004:Topoisomerase I Inhibitors
D000227:Adenine Nucleotides; D000998:Antiviral Agents; D004278:DNA, Superhelical; D009841:Oligonucleotides; D009843:Oligoribonucleotides; D059004:Topoisomerase I Inhibitors; C023505:2',5'-oligoadenylate