Multiple genetic mechanisms lead to loss of functional TbAT1 expression in drug-resistant trypanosomes

Stewart, M.L. et al. (2010) Multiple genetic mechanisms lead to loss of functional TbAT1 expression in drug-resistant trypanosomes. Eukaryotic Cell, 9(2), pp. 336-343. (doi: 10.1128/EC.00200-09) (PMID:19966032) (PMCID:PMC2823006)

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The P2 aminopurine transporter, encoded by TbAT1 in African trypanosomes in the Trypanosoma brucei group, carries melaminophenyl arsenical and diamidine drugs into these parasites. Loss of this transporter contributes to drug resistance. We identified the genomic location of TbAT1 to be in the subtelomeric region of chromosome 5 and determined the status of the TbAT1 gene in two trypanosome lines selected for resistance to the melaminophenyl arsenical, melarsamine hydrochloride (Cymelarsan), and in a Trypanosoma equiperdum clone selected for resistance to the diamidine, diminazene aceturate. In the Trypanosoma brucei gambiense STIB 386 melarsamine hydrochloride-resistant line, TbAT1 is deleted, while in the Trypanosoma brucei brucei STIB 247 melarsamine hydrochloride-resistant and T. equiperdum diminazene-resistant lines, TbAT1 is present, but expression at the RNA level is no longer detectable. Further characterization of TbAT1 in T. equiperdum revealed that a loss of heterozygosity at the TbAT1 locus accompanied loss of expression and that P2-mediated uptake of [3H]diminazene is lost in drug-resistant T. equiperdum. Adenine-inhibitable adenosine uptake is still detectable in a {Delta}Tbat1 T. b. brucei mutant, although at a greatly reduced capacity compared to that of the wild type, indicating that an additional adenine-inhibitable adenosine permease, distinct from P2, is present in these cells.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Burchmore, Dr Richard and Stewart, Dr Mhairi and Wong, Dr Pui Ee and MacLeod, Professor Annette and De Koning, Professor Harry and Tait, Professor Andy and Turner, Professor Charles and Barrett, Professor Michael and O'Connell, Dr Caroline
Authors: Stewart, M.L., Burchmore, R.J.S., Clucas, C., Hertz-Fowler, C., Brooks, K., Tait, A., MacLeod, A., Turner, C.M.R., De Koning, H.P., Wong, P.E., and Barrett, M.P.
Subjects:Q Science > QH Natural history > QH426 Genetics
Q Science > QH Natural history > QH301 Biology
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Eukaryotic Cell
ISSN (Online):1535-9786
Published Online:04 December 2009

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
271301Functional Characterisation of a Nucleoside Transporter in TrypanosomesMichael BarrettBiotechnology and Biological Sciences Research Council (BBSRC)17/C13486Infection Immunity and Inflammation Life Sciences