Poly(ADP-ribose) metabolism in human parasitic protozoa

Abstract

Poly(ADP-ribosyl)ation reactions constitute a post-translational protein modification synthesized in higher eukaryotes by a family of poly(ADP-ribose)polymerases (PARP) and catabolized mainly by poly(ADP-ribose) glycohydrolase (PARG). The best understood role of PARP is the maintenance of genomic integrity via the promotion of DNA repair that leads to cell survival when low levels of genotoxic stress occur. The participation of PARP in unleashing cell death at higher levels of damage has also been broadly studied. The biology of poly(ADP-ribosyl)ation in protozoan parasites, however, still remains a mystery. This review will examine the presence of the key enzyme involved in ADP-ribose polymer (PAR) metabolism in protozoan parasites associated with human diseases. Theoretical and experimental data obtained up to date have revealed the presence of PAR metabolism only in the trypanosomatids Trypanosoma cruzi and T. brucei, the apicomplexan Toxoplasma gondii and Entamoeba histolytica. T. cruzi and T. brucei, as opposed to humans and other organisms, have only one PARP and one PARG with subcellular localizations that are distinct from the ones described for their mammalian counterparts. The topics discussed in this review describe the first studies on PAR metabolism in trypanosomatids, specially the role of PAR on DNA damage response, cell cycle progression and cell death after genotoxic stimuli. The results described show differences in some aspects of PAR metabolism in trypanosomatids in comparison to other eukaryotes. New questions about the function of this metabolic pathway in the parasites under study are open and we hope it encourages the research community to explore this signaling pathway as a new possible target of clinical relevance in these and other disease-causing parasites.