Polyadenylation inhibition by the triphosphates of deoxyadenosine analogues.

Leukemia Research
Lisa S ChenVarsha Gandhi

Abstract

The nucleotide substrate specificity of yeast poly(A) polymerase (yPAP) was examined with various ATP analogues of clinical relevance. The triphosphate derivatives of cladribine (2-Cl-dATP), clofarabine (Cl-F-ara-ATP), fludarabine (F-ara-ATP), and related derivatives were incubated with yPAP and 32P-radiolabeled RNA oligonucleotide primers in the absence of ATP to assay polyadenylation. While 2-Cl-ATP resulted in primer elongation, ara-ATP and F-ara-ATP were poor substrates for yPAP. In contrast, the triphosphate derivatives of cladribine (2-Cl-dATP), clofarabine (Cl-F-ara-ATP) and its corresponding deoxyribose derivative (Cl-F-dATP) were substrates and caused chain termination in the absence of ATP. We further investigated whether analogue incorporation at the 3'-terminus of RNA primers negatively impacts polyadenylation with ATP by generating RNA oligonucleotides containing either a terminal clofarabine, Cl-F-dAdo, or cladribine residue. Incorporation of any of these analogs blocks the ability of yPAP to extend RNA past the analogue site, impeding the addition of a poly(A)-tail. To determine whether modified ATP analogues exhibit a concentration-dependent effect on polyadenylation, poly(A)-tail synthesis by yPAP with modified...Continue Reading

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Citations

Dec 9, 2009·Expert Opinion on Drug Metabolism & Toxicology·Patricia Hentosh, Dennis M Peffley
Sep 1, 2009·Expert Opinion on Investigational Drugs·Keeran SampatGautam Borthakur
Jul 7, 2009·Biochemical Pharmacology·Anna ZhenchukFreidoun Albertioni
Oct 10, 2009·Biochemical Pharmacology·Lisa S ChenVarsha Gandhi
Nov 1, 2011·Journal of Neuroimmunology·Bruno LaugelDenis Bruniquel
Mar 18, 2015·Bioorganic & Medicinal Chemistry·Kayla M BorlandVladislav A Litosh
Jan 19, 2019·Pharmaceutical Patent Analyst·Marcella Bassetto, Magdalena Slusarczyk
Jun 26, 2010·Environmental and Molecular Mutagenesis·Benigno C Valdez, Borje S Andersson
Sep 21, 2017·Future Medicinal Chemistry·Alessandra CavaliereMagdalena Slusarczyk

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