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Instituto de Parasitología y Biomedicina
"López - Neyra"
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ANTIGENIC VARIATION IN TRYPANOSOMA BRUCEI; NUCLEAR ARCHITECTURE, FACTORS AND REGULATION
Group Leader
    Miguel Angel Navarro Carretero     
Staff Research Posdoctoral
  • Carlos Cordón Obras     
Staff Research Predoctoral
  • Domingo Isaac Rojas Barros     
  • Manuel Alejandro Saldivia Concepción     
  • Andreu Saura Rebollar     
Technical Assistants
  • Isabel Beatriz Vidal Cobo     
Authorized Staff
  • Alejandro Aguilera Román     
  • Jean Mathieu Bart      
  • José Roberto Hernández Caicedo     

 

SUMMARY OF RESEARCH


 

 

By changes in the variant surface glycoprotein (VSG) coat, the bloodstream form of the parasite undergoes antigenic variation and eludes the host immune response. However, at a given time, only one VSG type is expressed on the surface of the cell. This is achieved by the transcription of only one telomeric expression site (ES) locus, out of twenty different ESs. Once active, high transcription of an ES is maintained during many generations. Previous work has shown that ES transcriptional activation can occur epigenetically, representing a genuine example of mono-allelic expression of a multigene family. We have recently obtained evidence that the recruitment of a single ES by a discrete transcriptional nuclear site, the ES Body, defines the mechanism responsible for VSG mono-allelic expresión (Navarro and Gull 2001). The main focus of our research is to investigate the unique transcriptional body we have recently identified in the nucleus of the protozoan parasite Trypanosoma brucei.

 

Nuclear architecture underlying developmentally regulated pol I transcription in Trypanosoma brucei

 

African trypanosomes are characterized by one of the more complex genetic mechanisms of immune-response evasion developed by a pathogen and serve as a model system for other parasites that undergo antigenic variation. Increasing interest in the significance of nuclear architecture in the regulation of gene expression makes Trypanosoma brucei an exceptional model system, since the two main surface-protein genes (VSGs and procyclin) are transcribed by the highly compartmentalized RNA polymerase I. In our lab we focus in understanding the influence of chromosomal nuclear spatial constraints in T. brucei transcriptional regulation.

Nuclear repositioning of chromosomes plays a significant role in accomplishing proper gene expression control. Accurate timing in the positioning of chromosome sites and association with particular nuclear structures are necessary to coordinate gene regulation. In the insect procyclic stage, non-excluding transcription of procyclin alleles appears to not be required for association with a single extranucleolar body, in contrast to the active VSG ES in the bloodstream form associated to the ES Body. Upon differentiation from the bloodstream to the insect procyclic stage the active VSG-ES promoter, previously, exclusively localized in the ESB, undergoes a rapid repositioning to the nuclear periphery with concomitant loss of the ESB. After repositioning, the active ES promoter undergoes chromatin condensation, as revealed by reduced accessibility of the GFP-lacI to Lac operator sequences inserted in the chromosome (Landeira and Navarro, 2007).

Our findings in trypanosome nuclear chromosome dynamics suggest that these phenomena are extremely conserved, since T. brucei is in a distal position in the eukaryotic cell linage. Nuclear envelope repositioning of chromosome loci in T. brucei influences pol I transcription suggesting nuclear architecture plays a global role in regulation of transcription in eukaryotes.

 


FUNDING AGENCIES LAST 5 YEARS

- RED RETICS. RED FIS, , Ref: RD12/0018/0015, (2013 - 2013).

- Identification of trypanocidal kinase inhibitors. PROYECTO, Convocatoria Tres Cantos Open Lab Foundation, Ref: PROJECT-TC007, (2011 - 2013).

- La quinasa TOR como diana terapéutica frente a enfermedades tropicales protozoarias.. PROYECTO, PROYEX-10, Ref: CTS-5841, (2011 - 2014).

- Análisis molecular y funcional de nuevos complejos TOR (Target Of Rapamycin) y nuevas rutas de señalización en tripanosomas africanos. PROYECTO, INV.FUND.NO ORIENTADA.- BIOMEDICINA, Ref: SAF2009-07587, (2010 - 2012).

- Red RICET. RED FIS, FONDO DE INVESTIGACION SANITARIA, Ref: RD06/0021/0010, (2007 - 2012).

- Caracterización funcional de TOR como diana terapéutica potencial en Trypanosoma brucei. PROYECTO, PROGRAMA NACIONAL DE BIOMEDICINA, Ref: SAF2006-01763, (2006 - 2009).

 

 

PUBLICATIONS LAST 5 YEARS

-Saldivia, M.; Barquilla, A.; Bart, J.-M.; Diaz-Gonzalez, R.; Hall, M.N.; Navarro, M., Target of rapamycin (TOR) kinase in Trypanosoma brucei: An extended family, Biochemical Society Transactions, 2013, Vol. 41: 934-938, ARTICULO    (Id en IPBLN: 1050)

-Cordon-Obras, C.; Cano, J.; González-Pacanowska, D.; Benito, A.; Navarro, M.; Bart, J.-M., Trypanosoma brucei gambiense adaptation to different Mammalian Sera is associated with VSG expression site plasticity, PLoS ONE, 2013, Vol. 8: null-, ARTICULO    (Id en IPBLN: 1059)

-Luque-Ortega, J.R.; De La Torre, B.G.; Hornillos, V.; Bart, J.-M.; Rueda, C.; Navarro, M.; Amat-Guerri, F.; Acuña, A.U.; Andreu, D.; Rivas, L., Defeating Leishmania resistance to Miltefosine (hexadecylphosphocholine) by peptide-mediated drug smuggling: A proof of mechanism for trypanosomatid chemotherapy, Journal of Controlled Release, 2012, Vol. 161: 835-842, ARTICULO    (Id en IPBLN: 891)

-Olmo, E.D.; Diaz-González, R.; Escarcena, R.; Carvalho, L.; Bustos, L.A.; Navarro, M.; Feliciano, A.S., Diamine and aminoalcohol derivatives active against Trypanosoma brucei, Bioorganic and Medicinal Chemistry Letters, 2012, Vol. 22: 440-443, ARTICULO    (Id en IPBLN: 892)

-Castillo-Acosta, V.M.; Aguilar-Pereyra, F.; Bart, J.-M.; Navarro, M.; Ruiz-Pérez, L.M.; Vidal, A.E.; González-Pacanowska, D., Increased uracil insertion in DNA is cytotoxic and increases the frequency of mutation, double strand break formation and VSG switching in Trypanosoma brucei, DNA Repair, 2012, Vol. 11: 986-995, ARTICULO    (Id en IPBLN: 916)

-DuBois, K.N.; Alsford, S.; Holden, J.M.; Buisson, J.; Swiderski, M.; Bart, J.-M.; Ratushny, A.V.; Wan, Y.; Bastin, P.; Barry, J.D.; Navarro, M.; Horn, D.; Aitchison, J.D.; Rout, M.P.; Field, M.C., NUP-1 is a large coiled-coil nucleoskeletal protein in trypanosomes with lamin-like functions, PLoS Biology, 2012, Vol. 10: null-, ARTICULO    (Id en IPBLN: 942)

-Barquilla, A.; Saldivia, M.; Diaz, R.; Bart, J.-M.; Vidal, I.; Calvo, E.; Hall, M.N.; Navarro, M., Third target of rapamycin complex negatively regulates development of quiescence in Trypanosoma brucei, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2012, Vol. 109: 14399-14404, ARTICULO    (Id en IPBLN: 973)

-Castillo-Acosta, V.M.; Aguilar-Pereyra, F.; Vidal, A.E.; Navarro, M.; Ruiz-Pérez, L.M.; González-Pacanowska, D., Trypanosomes lacking uracil-DNA glycosylase are hypersensitive to antifolates and present a mutator phenotype, International Journal of Biochemistry and Cell Biology, 2012, Vol. 44: 1555-1568, ARTICULO    (Id en IPBLN: 977)

-Klionsky, D.J.; Abdalla, F.C.; Abeliovich, H.; Abraham, R.T.; Acevedo-Arozena, A.; Adeli, K.; Agholme, L.; Agnello, M.;Agostinis, P.; Aguirre-Ghiso, J.A.; Ahn, H.J.; Ait-Mohamed, O.; Ait-Si-Ali, S.; Akematsu, T.o; Akira, S.; Al-Younes, H.M.; Al-Zeer, M.A.; Albert, M.L.; Albin, R.L.; Alegre-Abarrategui, J.; Aleo, M.F.; Alirezaei, M.; Almasan, A.; Almonte-Becerril; M.;González-Rey, E.; Hilfiker, S.;Navarro, M.;Oliver, F.J.; Campos-Salinas, J.;(...), Zschocke, J; Zuckerbraun, B, Guidelines for the use and interpretation of assays for monitoring autophagy, Autophagy, 2012, Vol. 8: 445-544, ARTICULO DE REVISION    (Id en IPBLN: 1063)

-Duszenko, M.; Ginger, M.L.; Brennand, A.; Gualdrón-López, M.; Colombo, M.-I.; Coombs, G.H.; Coppens, I.; Jayabalasingham, B.; Langsley, G.; De Castro, S.L.; Menna-Barreto, R.; Mottram, J.C.; Navarro, M.; Rigden, D.J.; Romano, P.S.; Stoka, V.; Turk, B.; Michels, P.A.M., Autophagy in protists, Autophagy, 2011, Vol. 7: 127-158, ARTICULO DE REVISION    (Id en IPBLN: 777)

-Navarro, M.; Peñate, X.; Landeira, D.; López-Farfán, D., Role of RPB7 in RNA pol i transcription in Trypanosoma brucei, Molecular and Biochemical Parasitology, 2011, Vol. 180: 45-46, CARTA AL EDITOR    (Id en IPBLN: 832)

-Diaz-Gonzalez, R.; Kuhlmann, F.M.; Galan-Rodriguez, C.; da Silva, L.M.; Saldivia, M.; Karver, C.E.; Rodriguez, A.; Beverley, S.M.; Navarro, M.; Pollastri, M.P., The susceptibility of trypanosomatid pathogens to PI3/mTOR kinase inhibitors affords a new opportunity for drug repurposing, PLoS Neglected Tropical Diseases, 2011, Vol. 5: -, ARTICULO    (Id en IPBLN: 850)

-De Jesus, T.C.L.; Tonelli, R.R.; Nardelli, S.C.; Da Silva Augusto, L.; Motta, M.C.M.; Girard-Dias, W.; Miranda, K.; Ulrich, P.; Jimenez, V.; Barquilla, A.; Navarro, M.; Docampo, R.; Schenkman, S., Target of rapamycin (TOR)-like 1 kinase is involved in the control of polyphosphate levels and acidocalcisome maintenance in Trypanosoma brucei, Journal of Biological Chemistry, 2010, Vol. 285: 24131-24140, ARTICULO    (Id en IPBLN: 748)

-Landeira, D.; Bart, J.-M.; Van Tyne, D.; Navarro, M., Cohesin regulates VSG monoallelic expression in trypanosomes, Journal of Cell Biology, 2009, Vol. 186: 243-254, ARTICULO    (Id en IPBLN: 615)

-Peñate, X.; López-Farfán, D.; Landeira, D.; Wentland, A.; Vidal, I.; Navarro, M., RNA pol II subunit RPB7 is required for RNA pol I-mediated transcription in Trypanosoma brucei, EMBO Reports, 2009, Vol. 10: 252-257, ARTICULO    (Id en IPBLN: 649)

-Barquilla, A.; Navarro, M., Trypanosome TOR as a major regulator of cell growth and autophagy, Autophagy, 2009, Vol. 5: 256-258, ARTICULO    (Id en IPBLN: 660)

-Barquilla, A.; Navarro, M., Trypanosome TOR complex 2 functions in cytokinesis, Cell Cycle, 2009, Vol. 8: 697-699, ARTICULO    (Id en IPBLN: 661)


 

 

DOCTORAL THESES LAST 5 YEARS

 

2013

Carlos Cordón Obras

Epidemiología de la Tripanosomiasis Humana Africana en los focos históricos de Guinea Ecuatorial y aproximación traslacional a la existencia de reservorios animales

Instituto de Parasitología y Biomedicina "López-Neyra" Universidad Complutense de Madrid - CSIC

 

 
2011

Diana Carolina López Farfán

Análisis de la función de la RPB7, la SUMO E3 ligasa SIZ1 y la SUMOilación de la cromatina en la regulación del sitio de expresión de la VSG en Tripanosoma brucei

Instituto de Parasitología y Biomedicina "López-Neyra" CSIC-Universidad de Granada

 

 
2009

Antonio A. Barquilla Panadero

Caracterización funcional de la proteína quinasa TOR (TargetofRapamycin) en T. brucei

Instituto de Parasitología y Biomedicina "López-Neyra" CSIC-Universidad de Granada

 

 

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