DNA damage and cell death pathways: role of poly(ADP-ribosyl)ation in Trypanosoma cruzi

SALOMÉ VILCHEZ LARREA; SANDRA PATRICIA CAIDEDO; GUILLERMO D. ALONSO; HÉCTOR N. TORRES; MIRTHA M. FLAWIÁ; SILVIA H. FERNÁNDEZ VILLAMIL

San Miguel de Tucumán, Tucumán, Argentina

Congreso; XLV Reunión Anual de la Sociedad Argentina de Investigaciones Bioquímicas (SAIB); 2009

Sociedad Argentina de Investigaciones en Bioquímica y Biología Molecular

The generation of genomic lesions triggers different pathways aimed at the restoration of the DNA integrity, except for those cases in which the extension of the damage impedes its reparation, ultimately unleashing cell death mechanisms. The poly(ADP-ribosyl)ation of nuclear proteins by the poly(ADP-ribose) polymerase (PARP) is a post-translational modification that occurs in response to DNA single strand breaks, allowing the recruitment and accession of repairing factors to the lesion site. In Trypanosoma cruzi, the only PARP present catalyzes the formation of poly(ADP-ribose) polymers (PAR) in a dose-dependent manner when epimastigotes are treated with H2O2 and UVC light. We have also found that PARP moves into the nucleus only after incubation with these agents; in contrast, poly(ADP-ribose) glycohydrolase (PARG) is present in the nucleus even in the absence of DNA damage, as opposed to what has been reported for other organisms. Above a certain threshold, these damaging agents can induce the death of the parasites, possibly through different mechanisms, as suggested by the different morphology observed and the determination of apoptotic and necrotic characteristics assessed by flow cytometry analysis. The importance of PAR in these pathways is reflected in the differential cell survival after treatment with these agents, either in presence or absence of PARP and PARG inhibitors.