dATP-mediated inhibition of DNA ligase by 2'-deoxycoformycin in T and B cell leukemia.
2'-Deoxycoformycin (dCF), a potent adenosine deaminase inhibitor, has been reported to display greater toxicity for T than for B lymphoblasts. Since this compound can block DNA replication and since this effect is mediated by the intracellular ATP/dATP balance, its possible effect on DNA ligase was investigated. dCF at relatively low concentrations (1 microM), in association with dATP (100 microM), is a strong inhibitor of DNA ligase in T blasts, whereas it has no significant effect in B blasts at this concentration. The AMP-ligase complex is the target of the observed inhibition because the combined presence of the inhibitor and dATP results in a more stable dAMP-ligase complex. Because of this observation and of the greater adenosine deaminase activity observed in T cells, the dATP mediated dCF inhibition of ligase might be the crucial replication target of T cell toxicity. These observations are discussed in terms of T immunodeficiencies including Graft Versus Host Disease and related syndromes.
Laboratoire de Biochimie du Développement, UA CNRS No. 256, Université de Rennes, France.
F
F
Lamballe
P Y
PY
Le Prise
E
E
Le Gall
J C
JC
David
D000255:Adenosine Triphosphate / Q000378:metabolism; D003070:Coformycin / Q000031:analogs & derivatives / Q000494:pharmacology*; D011088:DNA Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003838:Deoxyadenine Nucleotides / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D015448:Leukemia, B-Cell / Q000201:enzymology*; D015458:Leukemia, T-Cell / Q000201:enzymology*; D015649:Pentostatin; D011118:Polynucleotide Ligases / Q000037:antagonists & inhibitors*; D012263:Ribonucleosides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D003838:Deoxyadenine Nucleotides; D012263:Ribonucleosides; D003070:Coformycin; D015649:Pentostatin; D000255:Adenosine Triphosphate; D011088:DNA Ligases; D011118:Polynucleotide Ligases