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Genomes and Genes | RNA METABOLISM IN TRYPANOSOMESSummaryPrincipal Investigator: Elisabetta Ullu Abstract: DESCRIPTION (provided by the applicant): In the last few years the study of the biology of Trypanosoma brucei, the agent of sleeping sickness in humans and nagana in cattle, has witnessed an incredible growth due to two major advances: the completion of the T. brucei genome sequence and the discovery by our laboratory of RNA interference (RNAi). By interfacing genome information with down-regulating gene function by RNAi, it is now realistic to investigate complex cellular mechanisms using global approaches. As transcription regulation plays a minor role in T. brucei, the emphasis on regulation of gene expression is primarily on post-transcriptional regulatory mechanisms. Thus, we anticipate that the enzymes governing mRNA metabolism are essential for these parasites. This proposal focuses on aspects of RNA metabolism that are either unique to trypanosomes (cap 4 biosynthesis and function) or are novel concepts in eukaryotic biology (coupling of trans-splicing and polyadenylation and the RNAi pathway). The long-term goal of this proposal remains the characterization of molecular mechanisms involved in RNA metabolism and their relevance to trypanosome biology. In the next funding period we plan to: 1. Characterize the specific RNA methyltransferases involved in cap 4 biosynthesis and investigate whether there is a mechanistic link between cap 4 formation and polyadenylation. 2. Further our understanding of the coupling of trans-splicing and polyadenylation by using a variety of approaches, including monitoring the association of processing factors along transcribed genes in living cells. 3. Further characterize the RNAi pathway in terms of its components and how the interaction of TbAGO1 with translating ribosomes is brought about. Funding Period: 1989-12-01 - 2009-12-31 more information: NIH RePORT Top Publications
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Publications
On the extent and role of the small proteome in the parasitic eukaryote Trypanosoma bruceiMegan Ericson
Department of Epidemiology of Microbial Diseases, School of Public Health, Yale University, New Haven, CT, USA
BMC Biol 12:14. 2014..Such information can be particularly relevant to human pathogens, such as Trypanosoma brucei, the causative agent of African trypanosomiasis, since it will provide further insight into the parasite biology and life cycle...- The emerging world of small silencing RNAs in protozoan parasitesVanessa D Atayde
Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT 06536, USA
Trends Parasitol 27:321-7. 2011..In this article, we focus on the striking diversity of small silencing RNAs that have been identified in several protozoan parasites and their potential biological role... - Comparative genomics reveals two novel RNAi factors in Trypanosoma brucei and provides insight into the core machineryRebecca L Barnes
Department of Internal Medicine, Yale University, New Haven, Connecticut, USA
PLoS Pathog 8:e1002678. 2012..The availability of the core RNAi machinery in T. brucei provides a platform to gain mechanistic insights in this ancient eukaryote and to identify the minimal set of components required to reconstitute RNAi in RNAi-deficient parasites... - Small interfering RNA-producing loci in the ancient parasitic eukaryote Trypanosoma bruceiChristian Tschudi
Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT 06536, USA
BMC Genomics 13:427. 2012..Recent evidence from higher eukaryotes suggests that a variety of genomic sequences with the potential to produce double-stranded RNA are sources for small interfering RNAs (siRNAs)... - The structure and repertoire of small interfering RNAs in Leishmania (Viannia) braziliensis reveal diversification in the trypanosomatid RNAi pathwayVanessa D Atayde
Departments of Internal Medicine, Yale University, New Haven, CT 06536, USA
Mol Microbiol 87:580-93. 2013..Thus, our results indicate that organism-specific diversification has occurred in the RNAi pathway during evolution of the trypanosomatid lineage... - Developmental progression to infectivity in Trypanosoma brucei triggered by an RNA-binding proteinNikolay G Kolev
Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT 06536, USA
Science 338:1352-3. 2012..Thus, events leading to acquisition of infectivity in the insect vector are now accessible to laboratory investigation, providing an opening for new intervention strategies... - Role of the Trypanosoma brucei HEN1 family methyltransferase in small interfering RNA modificationHuafang Shi
Department of Internal Medicine, School of Medicine, Yale University, New Haven, Connecticut, USA
Eukaryot Cell 13:77-86. 2014..Moreover, expression of TbHEN1 in Leishmania (Viannia) panamensis did not result in siRNA 3' end methylation, further emphasizing mechanistic differences in the trypanosome and Leishmania RNAi mechanisms. .. - The emerging role of RNA-binding proteins in the life cycle of Trypanosoma bruceiNikolay G Kolev
Department of Epidemiology of Microbial Diseases, School of Public Health, Yale University, New Haven, CT, USA
Cell Microbiol 16:482-9. 2014..Here, we discuss recent progress in the identification of RBPs with crucial roles in different stages of the T. brucei life cycle, and in elucidating targets of RBPs. .. - RNA interference in protozoan parasites: achievements and challengesNikolay G Kolev
Department of Internal Medicine, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536 0812, USA
Eukaryot Cell 10:1156-63. 2011..Here we review the current status of RNAi in studies of parasitic protozoa, with special emphasis on its use as a postgenomic tool... - Retention and loss of RNA interference pathways in trypanosomatid protozoansLon Fye Lye
Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri, United States of America
PLoS Pathog 6:e1001161. 2010.... - The transcriptome of the human pathogen Trypanosoma brucei at single-nucleotide resolutionNikolay G Kolev
School of Public Health, Yale University, New Haven, Connecticut, United States of America
PLoS Pathog 6:e1001090. 2010..and revealed heterogeneity in pre-mRNA processing that could potentially contribute to the survival and success of the parasite population in the insect vector and the mammalian host... - Small nucleolar RNA interference in Trypanosoma brucei: mechanism and utilization for elucidating the function of snoRNAsSachin Kumar Gupta
The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar Ilan University, Ramat Gan 52900 Israel
Nucleic Acids Res 38:7236-47. 2010..snoRNAi of TB11Cs2C2 resulted in defects in generating srRNA-2 and LSUβ rRNA. This is the first snoRNA described so far to engage in trypanosome-specific processing events... - tRNASec is transcribed by RNA polymerase II in Trypanosoma brucei but not in humansEric Aeby
Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, CH 3012 Bern, Switzerland
Nucleic Acids Res 38:5833-43. 2010..Moreover, intron-encoded tRNAs are present in a number of eukaryotic genomes indicating that Pol-II transcription of tRNAs may not be restricted to trypanosomatids... 
Repression of gene expression by the coliphage MS2 coat protein in Trypanosoma bruceiHuafang Shi
Department of Internal Medicine, Yale Medical School, BCMM 136D, 295 Congress Avenue, Box 9812, New Haven, CT 06536 8012, USA
Mol Biochem Parasitol 144:119-22. 2005- Analysis of spliceosomal complexes in Trypanosoma brucei and silencing of two splicing factors Prp31 and Prp43Xue Hai Liang
Faculty of Life Sciences, Bar Ilan University, Ramat Gan 52900, Israel
Mol Biochem Parasitol 145:29-39. 2006..We identified a 45S complex carrying pre-mRNA and all the U-snRNAs, including U1 and the SL RNA, suggesting that a single spliceosomal complex may potentially conduct both trans- and cis-splicing... - A protein related to the vaccinia virus cap-specific methyltransferase VP39 is involved in cap 4 modification in Trypanosoma bruceiGeorge K Arhin
Department of Epidemiology and Public Health, Yale University Medical School, 295 Congress Avenue, New Haven, CT 06536 0812, USA
RNA 12:53-62. 2006..Interestingly, MT57 homologs are only found in trypanosomatid protozoa that have a cap 4 structure and in poxviruses, of which vaccinia virus is a prototype... - 2'-O-methylation of position 2 of the trypanosome spliced leader cap 4 is mediated by a 48 kDa protein related to vaccinia virus VP39George K Arhin
Department of Internal Medicine, Yale University Medical School, 295 Congress Avenue, New Haven, CT 06536 0812, USA
Mol Biochem Parasitol 147:137-9. 2006 - Functional replacement of Trypanosoma brucei Argonaute by the human slicer Argonaute2Huafang Shi
Department of Internal Medicine, Yale University Medical School, New Haven, Connecticut 06536, USA
RNA 12:943-7. 2006..This finding indicates that the basic features of the RNAi mechanism are conserved from T. brucei to man... - An unusual Dicer-like1 protein fuels the RNA interference pathway in Trypanosoma bruceiHuafang Shi
Department of Internal Medicine, Yale University Medical School, New Haven, Connecticut 06536 0812, USA
RNA 12:2063-72. 2006..This domain organization is specific to trypanosomatids and further illustrates the variable structures of protozoan Dicer-like proteins as compared to fungal and metazoan Dicer... - Genomic rearrangements and transcriptional analysis of the spliced leader-associated retrotransposon in RNA interference-deficient Trypanosoma bruceiKristin L Patrick
Department of Epidemiology and Public Health, Yale University Medical School, 295 Congress Avenue, New Haven, CT 06536 0812, USA
Mol Microbiol 67:435-47. 2008..We speculate that the small SLACS transcripts serve as substrates for the production of siRNAs to regulate SLACS expression... - The canonical pathway for selenocysteine insertion is dispensable in TrypanosomesEric Aeby
Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, CH 3012 Bern, Switzerland
Proc Natl Acad Sci U S A 106:5088-92. 2009..These results with T. brucei imply that eukaryotes have a single pathway of Sec-tRNA(Sec) synthesis that requires Sep-tRNA(Sec) as an intermediate... - Distinct and overlapping roles for two Dicer-like proteins in the RNA interference pathways of the ancient eukaryote Trypanosoma bruceiKristin L Patrick
Department of Epidemiology and Public Health, Yale University Medical School, 295 Congress Avenue, New Haven, CT 06536 0812, USA
Proc Natl Acad Sci U S A 106:17933-8. 2009..Our finding that dcl2KO cells are more sensitive to RNAi triggers than wild-type cells has significant implications for reverse genetic analyses in this important human pathogen... - RNA interference in Trypanosoma brucei: role of the n-terminal RGG domain and the polyribosome association of argonauteHuafang Shi
Department of Internal Medicine, Yale University Medical School, New Haven, Connecticut 06536 8012, USA
J Biol Chem 284:36511-20. 2009..This mechanism may represent an ancient adaptation to ensure that retroposon transcripts are efficiently destroyed, if they become associated with the translational apparatus... - Downregulation of the essential Trypanosoma brucei La protein affects accumulation of elongator methionyl-tRNAGeorge K Arhin
Department of Internal Medicine, Yale University Medical School, BCMM 136D, 295 Congress Avenue, Box 9812, New Haven, CT 06536 8012, USA
Mol Biochem Parasitol 144:104-8. 2005