Physiological interaction of BRCA2 and PARP in the protozoan pathogen Trypanosoma brucei

Abstract

Many eukaryotes including the parasitic protozoan Trypanosoma brucei depend heavily on the BRCA2 protein, which is important for the mediation of DNA recombination and repair. An interesting aspect of BRCA2 deficiency in cancer cells is that these cells are ultra‐sensitive to the inhibitors of the chromatin modifying enzyme poly(ADP‐ribose) polymerase (PARP). In the absence of PARP, spontaneous single‐strand breaks collapse replication forks and trigger homologous recombination for repair. Thus, PARP activity is essential in homologous recombination‐deficient BRCA2‐mutant cancer cells. BRCA2 and PARP are not only expressed in the mammalian cells but also present in high levels in many other eukaryotic cells including the parasitic protozoan T. brucei. To evaluate the universality of the importance of these two proteins in the management of DNA damage, we determined the effect of PARP inhibitors such as 3‐AB, Veliparib, PF‐01367338, Olaparib and Iniparib in BRCA2 knocked down T. brucei cells treated with the DNA damaging agent cisplatin. Our in vitro data strongly suggest that a combination of a BRCA2 inhibitor (e.g. BRCA2 BRC peptide), a PARP inhibitor and a DNA damaging agent (e.g. cisplatin) will be a chemical regimen for the management of trypanosomiasis and similar protozoan infections. Supported by NIH grants 2SC1GM081146‐05 to MC, 1U54RR026140‐01 to SM and NIH grants R01AI042327, R21AI076757 to GC.