RNA Abbau in Trypanosoma brucei

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In mammals, gene expression is controlled at multiple levels, including transcription, splicing, mRNA degradation and translation. In contrast, in African trypanosomes, the pathogens that cause sleeping sickness, mRNA levels are regulated almost exclusively via selective degradation. The unique dependence of the parasites on this one pathway not only makes the organisms an interesting model for the study of exoribonucleases, but also provides potential targets for anti-parasitic chemotherapy. We have previously characterised the trypanosome exosome, a complex which is responsible for 3'-5' RNA degradation, two trypanosome 5'-3' exonucleases (cytoplasmic XRNA and nuclear XRND), and two deadenylation complexes, CAF1/NOT and PAN2/3. All of these are essential for parasite survival. In trypanosomes, constitutive mRNA degradation of most mRNAs depends on deadenylation by the CAF1/NOT and PAN2/PAN3 complexes. The CAF1 protein is autonomously active as a deadenylase; in this proposal we wish to find out how the association of CAF1 with NOT1 and other proteins in a complex affects CAF1 activity, and determine the functions of the various subunits. Highly unstable trypanosome mRNAs are subjected to deadenylation-independent attack by XRNA, but there are also two other novel trypanosome-specific cytoplasmic 5'-3' exonucleases. Our second major aim is to determine the functions of these two proteins -XRNB, which has a zinc finger domain, and XRNC.