Noreen Williams, Ph.D.
Department of Microbiology & Immunology
Phone: (716) 829-2279
Fax: (716) 829-2158
Regulation of Gene Expression in Trypanosomes
Our laboratory uses molecular biological and biochemical approaches to study a group of parasitic protozoans that cause disease in humans and domestic animals in much of the tropical world. The major project focuses on Trypanosoma brucei, the causative agent of African sleeping sickness, which is transmitted by the tse-tse fly. Other projects focus on Trypanosoma cruzi, which causes Chagas disease in South and Central America and is transmitted by the reduviid bug. Treatment for these diseases is severely limited due to increasing drug resistance and issues of drug toxicity or lack of available drugs. The goal of our work is to discover and exploit critical events that occur in the parasite life cycle that may be used to prevent growth or transmission of the parasite.
The major project in the laboratory examines the ribosome, the complex molecular machine that drives protein synthesis. While many features of the ribosome and its assembly pathway are conserved in the parasites we study, we have identified a number of features in this pathway that are very different from the pathway in the human host. Our laboratory discovered a pair of trypanosome-specific RNA binding proteins, P34 and P37, which are essential to the formation of ribosomes only in these parasites. We have shown that these proteins interact with 5S rRNA and ribosomal protein L5 in a unique pre-ribosomal complex that is essential for ribosomal biogenesis and survival of the trypanosomes. Perhaps due to the presence of the trypanosome-specific proteins, P34 and P37, the normally conserved L5 protein also possesses unusual structural and functional characteristics. In addition, we have shown that P34 and P37 are required for the export of the large ribosomal subunit from the nucleus to the cytoplasm where it assembles into the fully functional ribosome required for protein synthesis.
The multiple roles of these trypanosome-specific proteins in the normally highly conserved pathway of ribosomal biogenesis is a surprising finding and may suggest that the interaction of these proteins with other components of the ribosomal assembly pathway can be developed as targets for chemotherapy. We have developed a fluorescence resonance energy transfer assay that allows us to study these interactions more closely. This method also allows us to develop a high throughput screen for small molecules that disrupt the complex in trypanosomes and do not harm the human host. Since little is known about the ribosome in trypanosomes, we are current collaborating in a project to examine the structure of the ribosome and intermediates in the pathway of assembly using cryo-EM. These experiments will provide important information about the unique features of the structure and function of the trypanosome ribosome. These studies will increase our understanding of the basic biology of the ribosome and further our discovery of potential drug targets.
More recently we have begun work characterizing this complex in the related parasite, T. cruzi with the idea that we may be able to use a similar approach to develop chemotherapeutic targets that would apply to the two related parasites, T. brucei and T. cruzi . In addition, we continue in a long standing collaboration with Dr. Beatriz Garat at the Universidad de la Républica in Uruguay, examining both DNA and RNA binding proteins which regulate gene expression in Trypanosoma cruzi.
Research and Professional Experience:
Professor [2002- present], Associate Professor [1998 - 2002], and Assistant Professor [1992 - 1998] Department of Microbiology, School of Medicine and Biomedical Sciences, University at Buffalo
Assistant Professor, Department of Biochemistry, Uniformed Services University of the Health Sciences, Bethesda, MD, 1987-1992
Postdoctoral Fellow/Research Associate, The McCollum-Pratt Institute and Department of Biology, Johns Hopkins University, Baltimore, MD, l984-1987, Research Advisor: Dr. Saul Roseman
Postdoctoral Fellow, Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 1981-1984, Research Advisor: Dr. Peter L. Pedersen
Chair, 2005-6 and member [2004-6] NIH Pathogenic Eukaryotes [formerly TMP] Study Section
Chair [2000-2001] and member [1996-2001], ad hoc [2001- present] NIH International and Cooperative Projects Study Section
Chair, NIH ICP Special Emphasis, Global Research Initiatives Program, 2002, 2003
Member, 2002-4 and ad hoc , NIH Tropical Medicine and Parasitology Study Section
Wellcome Trust Reviewer [ ad hoc ] 1999, 2002, 2003
Member, Editorial Board, Journal of Bioenergetics and Biomembranes, 1991-present Peer Reviewer ( ad hoc ), J. Biological Chemistry, Mol. Biochem. Parasitol., Can. J. Physiology and Pharmacology, J. Euk. Microbiology, Molecular and Cell Biology, Eukaryotic Cell
Ellison Visiting Scholar, Marine Biological Laboratories, 2003
National Research Service Award, National Institute of General Medical Sciences, 1984-1986
Brown B., S.V., Stanislawski, A., Perry, Q. L., and Williams, N . (2001) Cloning and characterization of the subunits comprising the catalytic core of the Trypanosoma brucei ATP synthase Mol. Biochem. Parasitol. 113:289-301.
Brown B., S.V., Chi, T.B., and Williams, N. (2001) The mitochondrial ATP synthase is developmentally regulated at the level of transcript stability. Mol. Biochem. Parasitol .15: 177-187.
Pitula, J., Ruyechan, W.T., and Williams, N . (2002) Two novel RNA binding proteins from T. brucei are associated with 5S rRNA Biochem. Biophys. Res. Commun . 290: 569-576 .
Pitula, J., Park, J., Parsons, M., Ruyechan, W.T., and Williams, N . (2002) Two families of RNA binding proteins in T. brucei associate in a direct protein-protein interaction. Mol. Biochem. Parasitol . 122: 77-85.
Li, J. Ruyechan, W.T., and Williams, N . (2003) Stage specific translational efficiency and protein stability regulate the developmental expression of p37, an RNA binding protein from Trypanosoma brucei . Biochem. Biophys. Res. Commun. 306: 918-923.
Duhagon, M.A., Dallagiovanna, B., Ciganda, M., Ruyechan, W., Williams, N ., and Garat, B. (2003) A novel type of single-stranded nucleic acid binding protein recognizing a highly frequent motif in the intergenic regions of Trypanosoma cruzi . Biochem. Biophys. Res. Commun. 309: 183-188.
Gomes, G., Ürményi, T., Rondenelli, E., Williams, N ., and Silva, R. (2004) RNA binding proteins TcRRM1 and TcRRM2 and an unknown gene Tc28 are intercalated in the genome and are differentially expressed during the life cycle of Trypanosoma cruzi . Biochem. Biophys. Res. Commun. 322: 985-992.
Brown, S.V., Hosking, P., Li, J.L., and Williams, N . (2006) The Mitochondrial ATP Synthase is responsible for maintenance of membrane potential in bloodstream T. brucei . Euk. Cell 5: 45-53.
Pérez-Díaz, L., Duhagon , M., Smircich, P., Sotelo-Silveira, J., Robello, C. , Krieger, M., Goldenberg, S., Williams, N., Dallagiovanna, B. and Garat, B. (2007) Trypanosoma cruzi: Molecular characterization of an RNA binding protein differentially expressed in the parasite life cycle. Exp. Parasitol. 117: 99-105.
Hellman, K., Ciganda, M., Brown, S.V., Li, J.L., Ruyechan, W.T., and Williams N (2007) Two trypanosome-specific proteins are essential factors for 5S rRNA abundance and ribosomal assembly in T. brucei Euk. Cell 6: 1766-17772.
Hellman, K., Prohaska, K., and Williams, N. (2007) T. brucei RNA binding proteins, p34 and p37, mediate NOPP44/46 localization via the exportin 1 pathway. Euk. Cell 6: 2206-2213.
Prohaska, K. and Williams, N. (2009) Assembly of the Trypanosoma brucei 60S ribosomal subunit nuclear export complex requires trypanosome-specific proteins P34 and P37. Euk. Cell 8: 77-87.
Duhagon, M., Sotelo-Silveira, J., Pastro, L., Pérez-Díaz, L., Maugeri, D., Williams, N., Dallagiovanna, B., and Garat, B. (2009) The Trypanosoma cruzi nucleic acid binding protein Tc38 presents changes in the intramitochondrial distribution during the cell cycle. BMC Microbiology 9:34 [PMID: 19210781]
Duhagon, MA, Smircich, P, Forteza, D, Naya, H, Williams N, and Garat B. (2011) Comparative Genomic Analysis of dinucleotide repeats in Tritryps. Gene. 487(1):29-37. [PMID: 21824509]
Ciganda, M, Williams, N. (2011) Eukaryotic 5S rRNA biogenesis. Wiley Interdiscip Rev RNA. 2:523-33. [PMID: 21957041]
Ciganda, M, and Williams, N. (2012) Characterization of a novel association between two trypanosome-specific proteins and 5S rRNA. PLoS One. 2012;7(1):e30029. [PMID: 22253864]
Ciganda, M, Prohaska, K, Hellman, K and Williams, N. (2012) A novel association between two trypanosome-specific factors and the conserved L5-5S rRNA complex PLoS One 7:e41398. [PMID: 22859981]
Gulde, P, Brown, S, and Williams, N. (2013) Three distinct isoforms of ATP synthase subunit c are expressed in T. brucei and assembled into the mitochondrial ATP synthase complex. PLoS One. 2013;8:e54039. [PMID:23326569]
Wang, L, Ciganda, M, and Williams, N. (2013) Association of a novel pre-ribosomal complex in T. brucei determined by fluorescence resonance energy transfer. Eukaryot Cell. 12:322-9. [PMID:23264640]
Sakayiama, J, Zimmer, SL, Ciganda, M, Williams, N, and Read, L (2013) Ribosome biogenesis requires a highly diverged XRN family 5’->3’ exoribonuclease for rRNA processing in Trypanosoma brucei. RNA 19:1419-31 [PMID:23974437]
Wang, L, Ciganda, M, and Williams, N (2013) Defining the RNA-protein interactions in the trypanosome preribosomal complex. Eukaryot Cell 12:559-66. [PMID:23397568] Selected for Spotlight feature, Papers of significant interest to editors
Umaer K, Ciganda M, Williams N, (2014) Ribosome biogenesis in African trypanosomes requires conserved and trypanosome-specific factors. Eukaryot Cell. [Epub ahead of print] [PMID:24706018]Selected for Spotlight feature, Papers of significant interest to editors