Noreen Williams, Ph.D.
Department of Microbiology & Immunology
Phone: (716) 829-2279
Fax: (716) 829-2158
Developmental 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. Two projects focus 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 regulatory events that occur in the parasite life cycle that may be used to prevent growth or transmission of the parasite.
The first project, examines a pair of unique RNA binding proteins, P34 and P37, which are highly homologous to one another. We have shown that these proteins interact with 5 S rRNA and ribosomal protein L5 in a unique pre-ribosomal complex that is essential for ribosomal biogenesis and survival of the trypanosomes. The role of these trypanosome-specific proteins in the normally highly conserved pathway of ribosomal biogenesis is a surprising finding and may suggest that these proteins and the pre-ribosomal complex could be developed as targets for chemotherapy. In addition, we have studied these proteins as models for mechanisms of developmental regulation in trypanosomes. We have developed a fluorescence resonance energy transfer assay that allows us to study the interactions within the pre-ribosomal complex and 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. We have also begun work characterizing this complex in the related parasite, T. cruzi.
The second project centers on the mitochondrial ATP synthase of T. brucei. This protein complex couples the energy generated by the electron transport chain to the synthesis of ATP. In T. brucei we have shown that the ATP synthase is regulated through the life cycle of the organism by several unique mechanisms which appear to be different from the regulatory mechanisms for other mitochondrial proteins such as those in the electron transport chain. This regulation may be critical to understanding how this parasite responds to change in the environment due to the two host organisms (in this case, the tsetse fly and the cow). We have shown that the ATP synthase is responsible for maintaining a mitochondrial membrane potential in the bloodstream stage of the parasite. This membrane potential is required for the parasite’s survival since without it the parasite cannot pre-adapt for survival in the insect vector. Recently we have shown that the F0 membrane component is comprised of three different c subunits, suggesting that this may provide an adaptive response under different environmental confditins. These results suggest that the ATP synthase may provide an excellent target for drug development focused on preventing transmission of the parasite by the insect.
In the third project in long standing collaboration with Dr. Beatriz Garat at the Universidad de la Républica in Uruguay, we are 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]
Wang, L, Ciganda, M, and Williams, N. (2013) 5S rRNA enhances the protein-protein interactions in the T. brucei pre-ribosomal complex
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 (in submission)