Poly(ADP-ribosyl)ation is a post-translational modification carried out by members of de poly(ADP-ribose)polymerase (PARP) family. These polymers are involved in various cellular processes including DNA damage signaling and repair, cell cycle regulation, cell differentiation and cell death pathways. This modification is transient, being poly(ADP-ribose)glycohydrolase the main degrading enzyme.

The parasites Trypanosoma cruzi and Trypanosoma brucei bear only one copy of these enzymes, differing from other organisms. These enzymes also have different localization and activity requirements than those described for their mammalian counterparts. These pose them as putative therapeutic targets, encouraging the search for inhibitors of this pathway that are specific for these trypanosomatids.

Lab Members

Publications

Structural and Biochemical Characterization of Poly-ADP-ribose Polymerase from Trypanosoma brucei.
Haikarainen T, Schlesinger M, Obaji E, Fernández Villamil SH,  Lehtiö L
Sc entific Reports; Año: 2017

Poly(ADP-ribosylation) is present in murine sciatic nerve fibers and is altered in a Charcot-Marie-Tooth-1E neurodegenerative model.
Lafon Hughes L, Romero Cardeillac CJ, Cal Castillo KB, Vilchez Larrea SC, Sotelo Sosa J, Folle Ungo G, Fernandez Villamil SH, Kun Gonzalez A.
PeerJ; Año: 2017 vol. 5
Disrupted ADP-ribose metabolism with nuclear Poly (ADP-ribose) accumulation leads to different cell death pathways in presence of hydrogen peroxide in procyclic Trypanosoma brucei.

Schlesinger M, Vilchez Larrea SC, Haikarainen T, Narwal M, Venkannagari H, Flawia MM,  Lehtiö L, Fernández Villamil SH.
Parasites and Vectors. (2016) 9:173. DOI 10.1186/s13071-016-1461-1 marzo 2016.

VERO cells harbor a poly-ADP-ribose belt partnering their epithelial adhesion Belt. Lafon Hughes L, Vilchez Larrea SC, Kun A, Fernández Villamil SH. 1.
PeerJ 2:e617 http://dx.doi.org/10.7717/peerj.617 oct 2014.

Host Cell Poly(ADP-ribose) glycohydrolase Is Crucial for Trypanosoma cruzi  Infection Cycle. Vilchez Larrea SC, M, Schlesinger M, Kevorkian ML, Flawia MM,  Alonso GD, Fernández Villamil SH.
PLoS ONE, vol 8 issue 6, 2013.

The metabolism of 9-chloro-β-lapachone and its effects in isolated hepatocytes. The involvement of NAD(P)H: quinone oxidoreductase 1 (NQO1). Fernández Villamil SH, Carrizo P, Di Rosso E, Molina Portela MP and Dubin M.
Chem Biol Interact. 200(2-3):84-91, 2012.

Inhibition of poly(ADP-ribose) polymerase interferes with Trypanosoma cruzi infection and proliferation of the parasite.
Vilchez Larrea SC, Haikarainen T, Narwal M, Schlesinger M, Venkannagari H, Flawia MM,  Fernández Villamil SH, Lehtiö L.
PLoS ONE, vol 7 issue 9, 2012.

Poly(ADP-ribose)polymerase plays a diffrential role in DNA damage response and cell death pathways in Trypanosoma cruzi.
Vilchez Larrea SC, Alonso GD, Schlesinger M, Torres HN, Flawiá MM and Fernández Villamil SH.
International Journal for Parasitology, 41: 405-416, 2011.

Metabolism of Poly-ADP-ribose in Trypanosomatids.
Alonso GD, Vilchez Larrea SC and Fernández Villamil SH.
Parasitology Research Trends. Ed: Olivier De Bruyn and Stephane Peeters. 6: 1-11, 2010.

TcPARP: A DNA damage-dependent poly(ADP-ribose)polymerase from Trypanosoma cruzi. Fernández Villamil SH, Baltanás R, Alonso GD, Vilchez Larrea SC, Torres HN, Flawiá MM.
International Journal for Parasitology, 38: 277–287, 2008.

Research Lines

 Structural and metabolic studies of poly(ADP-ribose)polymerase (PARP) and poly(ADP-ribose)glycohydrolase (PARG) enzymes from T. cruzi and T brucei

One of our working subjects is the study of PARP and PARG and the role of poly(ADP-ribose) on cell cycle, DNA damage response and immune system evasion in the different forms of these parasites.

 

Nuclear PAR generated by genotoxic stress in T. cruzi epimastigotes and blood stream form of Trypanosoma brucei

 

 Role of polymers of ADP-ribose during the host cell response elicited by T. cruzi infection 

A new focus has been placed on unravelling the participation of ADP-ribose polymer metabolism in the host cell during the infection process and the immflamatory response mediated by PAR.

 

 

 Trypanosoma cruzi amastigotes in HL-1 cells

 Membrane associated ADP-ribose polymers and their role during T. cruzi invasion 

 We seek to study PAR metabolism associated with intercellular  junctions and deciphering which PARPs might be involved and their possible targets, focusing on the dynamics triggered by T cruzi invasión.

 

Vero cells: actin microfilaments (red), PAR (green) in epithelial adhesion belt

 

Ex Lab Members

Dra. Dolores Podesta
Dr. Rodrigo Baltanas
Dra. Patricia Caicedo Burbano
Dra. Mariana Schlesingher

  • Biochemist. School of Pharmacy and Biochemistry University of Buenos Aires, Argentine.
  • PhD in Biochemistry. University of Buenos Aires, Argentine.
  • Member of the Research Career in the National Research Council of Argentina (CONICET): Rank 3 of 5.
  • Assistant Professor, Department of Biological Chemistry.  School of Pharmacy and Biochemistry. University of Buenos Aires.
  • Member of the Argentinean Society of Biochemist Research and Molecular Biology.Member of the Argentinean Society of Protozoology.