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Poly(A)+RNA as a Possible Target for Deoxyadenosine Induced G1/G0 Lymphotoxicity

  • R. F. Kefford
  • R. M. Fox
  • E. McCairns
  • D. Fahey
  • G. E. O. Muscat
  • P. B. Rowe
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 165)

Abstract

In the presence of inhibitors of the enzyme adenosine deaminase (ADA), micromolar concentrations of 2′-deoxyadenosine (dAdo) are toxic to cultured T-leukemic lymphoblasts1. Lymphotoxicity has been attributed to allosteric inhibition of ribonucleotide reductase by accumulated dATP, with resultant inhibition of DNA synthesis. There is now evidence, however, that dAdo is lymphotoxic independent of any inhibition of DNA synthesis.In the presence of ADA inhibitors, micromolar concentrations of dAdo are toxic to non-dividing human lymphoid cells3,4, and human T-lymphoblasts exposed to cytostatic concentrations of dAdo arrest in G1 phase5. We sought to determine if these effects of dAdo were due to effects of dATP on polyadenylated (poly(A)+)RNA metabolism, analogous to the effects of 3′-dAdo (cordycepin). The cordycepin metabolite, 3′-dATP, preferentially inhibits the synthesis and polyadenylation of poly (A)+ RNA and there is evidence that 3′-dATP is incorporated at the 3′terminus of poly(A) segments, leading to premature chain termination6,7. Despite marked differences in the gross DNA/RNA perturbations seen in dAdo and cordycepin treated cells, we show that dAdo is also terminally incorporated into poly(A) segments, suggesting another possible mechanism for dAdo lymphotoxicity.

Keywords

Ribonucleotide Reductase Purine Nucleoside Purine Nucleoside Phosphorylase Ribonucleotide Reductase Inhibition Adenosine Deaminase Deficiency 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science+Business Media New York 1984

Authors and Affiliations

  • R. F. Kefford
    • 1
  • R. M. Fox
    • 1
  • E. McCairns
    • 2
  • D. Fahey
    • 2
  • G. E. O. Muscat
    • 2
  • P. B. Rowe
    • 2
  1. 1.Ludwig Institute for Cancer ResearchSydney BranchAustralia
  2. 2.Children’s Medical Research FoundationUniversity of Sydney, NSW, 2006Australia

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