RESEARCH INTERESTS:
We are studying the biogenesis, trafficking and function of non-coding RNA-protein complexes with the goal of improving the understanding and treatment of human disease.

• Overview (non-coding RNAs): The numerous cellular RNAs that do not encode proteins but function directly in diverse cellular processes (a.k.a. non-coding RNAs) are one of the most exciting areas of research in biology today. Our appreciation of the numbers and importance of these RNAs has exploded in recent years. ncRNAs include telomerase, microRNAs, siRNAs, viroids, and snoRNAs. Most of these RNAs function as part of RNA-protein complexes. Our lab studies the biogenesis, assembly, trafficking, and function of ncRNA-protein complexes (RNPs). Our work has direct links to the etiology and treatment of cancer and to the development of anti-microbial agents.
• Telomerase and cancer: We are investigating the regulation of the biogenesis and transport of the telomerase RNP, a key molecule in the processes of aging and cancer. Telomerase maintains telomeres at the ends of chromosomes. Telomerase activity and telomere length are lost with aging, resulting in cell senescence and death. In order to be able to grow indefinitely, nearly all cancer cells re-activate telomerase. Thus telomerase is a promising target for anti-cancer and anti-aging therapies. In cancer cells, we have found that the two essential components of telomerase (telomerase RNA and TERT) travel distinct, cell cycle-regulated pathways within the nucleus that culminate in co-localization at telomeres during S phase for telomere synthesis. We are working to identify the factors responsible for the regulated activity of telomerase in normal and cancer cells.
• Virus defense in prokaryotes: All bacteria (including human pathogens) are subject to attack by viruses and other genome invaders. We are working to delineate a newly-identified RNA-mediated pathway that protects bacteria and archaea from viruses and other invaders. The pathway appears to parallel the eukaryotic RNAi pathway and is referred to as "prokaryotic RNAi". This is a very exciting new research area with significant biomedical and biotechnological importance.
• snoRNAs: Small nucleolar RNAs are trans-acting RNAs that guide the modification and cleavage of other cellular RNAs. In previous work, we uncovered the pathways that snoRNAs travel within the nucleus and identified the RNA motifs that direct their transport. The motifs that we identified also have the ability to localize foreign RNAs. Breakthrough studies from our group revealed the essential components and organization of a major class of snoRNA-protein complexes (snoRNPs), the H/ACA RNP. In addition, our work provided the initial evidence that the spinal muscular atrophy disease protein (SMN) may function in the assembly of snoRNPs.
• non-coding RNAs in archaea: The archaea provide a fantastic model system for the study of ncRNPs, many of which are fundamentally similar to those found in eukaryotes, but have biochemical properties that expedite progress and interesting distinctions that provide evolutionary insights. For example, our studies of the archaeal H/ACA RNP revealed a structural domain of the Cbf5 protein associated with development of dyskeratosis congenita in humans. In addition, the archaea possess distinct classes of ncRNPs with functions that have yet to be determined.

CURRENT FUNDING:

• National Institutes of Health (NIH) for non-coding RNA-protein complex projects.
• National Cancer Institute (NIH) for telomerase projects.
• National Cancer Institute (NIH) supplemental funding to promote diversity in health-related research.
• The Nora L. Redman Fund for investigation of the etiology and treatment of childhood diseases.

SELECTED PUBLICATIONS:

• Liang B, Zhou J, Kahen E, Terns RM, Terns MP, Li H. (2009) Structure of a functional ribonucleoprotein pseudouridine synthase bound to a substrate RNA. Nat Struct Mol Biol., in press. Read Liang et al.
• Venteicher, A.S., Abreu, E.A., Meng, Z., McCann, K.E., Terns, R.M., Veenstra, T.D., Terns, M.P., Artandi S.E. (2009) A telomerase holoenzyme protein required for Cajal body localization and telomere synthesis. Science, 323(5914):644-8. Read Venteicher et al.
• Carte, J., Wang, R., Li, H., Terns, R.M. and Terns, M.P. (2008) Cas6 is an Endoribonuclease that Generates Guide RNAs for Invader Defense in Prokaryotes. Genes & Development, 22:3489-3496. Read Carte et al.
• Hale, C., Kleppe, K., Terns, R.M. and Terns, M.P. (2008) Prokaryotic silencing (psi)RNAs in Pyrococcus furiosus. RNA, 14(12):2572-9. Read Hale et al.
• Tomlinson, R., Abreu, E., Ziegler, T., Ly, H., Counter, C., Terns, R.M., Terns, M.P. (2008) Telomerase reverse transcriptase is required for the localization of telomerase RNA to Cajal bodies and telomeres in human cancer cells, Molecular Biology of the Cell, (9):3793-800. Read Tomlinson et al.
• Baker, D.L., Seyfried, N.T., Li, H., Orlando, R., Terns, R.M., Terns, M.P. (2008) Determination of protein-RNA interaction sites in the Cbf5-H/ACA guide RNA complex by mass spectrometric protein footprinting, Biochemistry, (6):1500-10. Read Baker et al.
• Qiu, H., Eifert, J., Wacheul, L., Thiry, M., Berger, A.C., Woolford, J.L., Corbett, A.H., Lafontaine, D.L.J., Terns, R.M., and Terns, M.P. (2008) Identification of genes that function in the biogenesis and localization of small nucleolar RNAs in Saccharomyces cerevisiae, Molecular & Cellular Biology, 28(11):3686-99. Read Qiu et al.
• Liang, B., Xue, S., Terns, R.M., Terns, M.P. Li, H. (2007) Substrate RNA Positioning in the Archaeal H/ACA Ribonucleoprotein Complex. Nature Structural and Molecular Biology, 14:1189 - 1195. Read Liang et al.
• Youssef, O.A., Terns, R.M., Terns, M.P. (2007) Dynamic interactions within sub-complexes of the H/ACA pseudouridylation guide RNP, Nucleic Acids Research, 35(18):6196-206. Read Youssef et al.
• Cristofari, G., Adolf, E., Reichenbach, P., Sikora, K., Terns, R.M., Terns, M.P., and Lingner J. (2007) Human telomerase RNA accumulation in Cajal bodies facilitates telomerase recruitment to telomeres and telomere elongation. Molecular Cell, 27(6):882-9. Read Cristofari et al.
• Oruganti, S., Zhang, Y., Li, H., Robinson, H., Terns, M.P, Terns, R.M., Yang W., and Li H. (2007) Alternative conformations of the archaeal Nop56/58-fibrillarin complex imply flexibility in box C/D RNPs. Journal of Molecular Biology, 371(5):1141-50. Read Oruganti et al.
• Matera, A.G., Terns, M.P., and Terns, R.M. (2007) Noncoding RNAs: Lessons from the snRNAs and snoRNAs. Nature Reviews Molecular Cell Biology, 8(3):209-20. Read Matera, Terns and Terns.
• Terns, M.P., and Terns, R.M. (2006) Non-Coding RNAs of the H/ACA Family. 71st Cold Spring Harbor Laboratory Symposium on Quantitative Biology: Regulatory RNAs, 71:395-405. Read Terns and Terns.
• Roovers, M., Hale, C., Tricot, C., Terns, M.P., Terns, R.M., Grosjean, H., and Droogmans, L. (2006) Formation of the conserved pseudouridine at position 55 in archaeal tRNA. Nucleic Acids Research, 34(15):4293-301. Read Roovers et al.
• Rashid, R., Liang, B., Baker, D.L., Youssef, O.A., He, Y., Phipps, K., Terns, R.M., Terns, M.P., Li, H. (2006) Crystal Structure of a Cbf5-Nop10-Gar1 Complex and Implications in RNA-Guided Pseudouridylation and Dyskeratosis Congenita. Molecular Cell, 21(2):249-60. Read Rashid et al.
• Tomlinson, R.L., Ziegler, T.D., Supakorndej, T., Terns, R.M., and Terns, M.P. (2005) Cell cycle regulated trafficking of human telomerase to telomeres. Molecular Biology of the Cell, 17(2):955-65. Read Tomlinson et al.
• Baker, D.L., Youssef, O.A., Chastkofsky, M.I.R., Dy, D., Terns, R.M., and Terns, M.P. (2005) RNA-Guided RNA Modification:Functional Organization of the Archaeal H/ACA RNP. Genes & Development, 19(10):1238-48. Read Baker et al.
• Yu, Y.T., Terns, R.M., and Terns, M.P. (2005) Mechanisms and Functions of RNA-guided RNA Modification. "Topics in Current Genetics" vol 12, Springer-Verlag, NY, H. Grosjean ed., pp. 223-262. Read Yu et al.
• Starostina, N.G., Marshburn, S., Johnson, L.S., Eddy, S.R., Terns, R.M., and Terns, M.P. (2004) Circular Box C/D RNAs in Pyrococcus furiosus. Proceedings of the National Academy of Sciences, 101(39):14097-101. Read Starostina et al.
• Deng L, Starostina NG, Liu ZJ, Rose JP, Terns RM, Terns MP, Wang BC. (2004) Structure determination of fibrillarin from the hyperthermophilic archaeon Pyrococcus furiosus. Biochem Biophys Res Commun. 315(3):726-32. Read Deng et al.
• Leary, D. J., Terns, M. P., and Huang, S. (2003) Components of U3 snoRNA Containing Complexes Shuttle Between Nuclei and the Cytoplasm and Differentially Localize in Nucleoli: Implications for Assembly and Function. Molecular Biology of the Cell, 15(1):281-93. Read Leary et al.
• Zhu, Y., Tomlinson, R., Lukowiak, A., Terns, R. M., and Terns, M. P. (2003) Telomerase RNA Accumulates in Cajal bodies in Human Cancer Cells. Molecular Biology of the Cell, 15(1):81-90. Read Zhu et al.
• Zhao, X., Li, Z.-H., Terns, R. M., Terns, M. P., and Yu, Y.-T. (2002) An H/ACA guide RNA directs U2 pseudouridylation at two different sites in the branch point recognition region in Xenopus oocytes. RNA, 8(12):1515-25. Read Zhao et al.
• Whitehead SE, Jones KW, Zhang X, Cheng X, Terns RM, Terns MP. (2002) Determinants of the interaction of the spinal muscular atrophy disease protein SMN with the dimethylarginine-modified Box H/ACA snoRNP protein GAR1. Journal of Biological Chemistry, 277(50):48087-93. Read Whitehead et al.
• Narayanan A, Eifert J, Marfatia KA, Macara IG, Corbett AH, Terns RM, and Terns MP. (2002) Nuclear RanGTP is Not Required for Targeting Small Nucleolar RNAs to the Nucleolus. Journal of Cell Science, 116:177-186. Read Narayanan et al.
• Cahill NM, Friend K, Speckmann W, Li ZH, Terns RM, Terns MP, Steitz JA. (2002) Site-specific cross-linking analyses reveal an asymmetric protein distribution for a box C/D snoRNP. EMBO Journal, 21(14):3816-28. Read Cahill et al.
• Etheridge KT, Banik SS, Armbruster BN, Zhu Y, Terns RM, Terns MP, Counter CM. (2002) The nucleolar localization domain of the catalytic subunit of human telomerase. Journal of Biological Chemistry, 277(27):24764-70. Read Etheridge et al.
• Speckmann, W., Li, Z-H., Lowe, T., Eddy, S., Terns, R. M., and Terns, M. P. (2002) Archaeal Guide RNAs Function in rRNA Modification in the Eukaryotic Nucleus. Current Biology, 12(3):199-203. Read Speckmann et al.
• Terns, M. P., and R.M. Terns (2002) Small Nucleolar RNAs: Versatile Trans-Acting Molecules of Ancient Evolutionary Origin. Gene Expression, 10(1-2):17-39. Read Terns and Terns
• Lukowiak, A. A., Narayanan, A., Li, Z., Terns, R. M., and Terns, M. P. (2001) The snoRNA domain of human telomerase RNA functions to localize the RNA within the nucleus. RNA, 7:1833-1844. Read Lukowiak et al.
• Terns, M. P., and R.M. Terns (2001) Macromolecular complexes: SMN - the master assembler. Current Biology, 11:R862–R864. Read Terns and Terns
• Jones, K.W., Gorzynski, K., Hales, C.M., Fischer, U., Badbanchi, F., Terns, R. M., and Terns, M. P. (2001) Direct interaction of the spinal muscular atrophy disease protein SMN with the small nucleolar RNA-associated protein fibrillarin. Journal of Biological Chemistry, 276:38645-38651. Read Jones et al.
• Yu, Y., Shu, M., Narayanan, A., Terns, R.M., Terns, M.P., and Steitz, J.A. (2001) Internal modification of U2 snRNA occurs in nucleoli of Xenopus oocytes. Journal of Cell Biology, 152:1279-1288. Read Yu et al.
• Speckmann, W., Terns, R. M., and Terns, M. P. (2000) The Box C/D motif targets 5' cap hypermethylation of small nucleolar RNAs. Nucleic Acids Research 28: 4467-4473. Read Speckmann et al.
• Lukowiak, A., Granneman, S., Mattox, S., Speckmann, W., Jones, K., Pluk, H., van Venrooij, W., Terns, R. M., and Terns, M. P. (2000) Interaction of the U3-55k protein with U3 snoRNA is mediated by the Box B/C motif of U3 and the WD40 repeats of U3-55k. Nucleic Acids Research 28: 3462-3471. Read Lukowiak et al.
• Speckmann, W., Narayanan, A., Terns, R. M., and Terns, M. P. (1999) Nuclear retention elements of U3 small nucleolar RNA. Mol. Cell. Biol. 19:8412-8421. Read Speckmann et al.
• Narayanan, A., Lukowiak, A., Jady, B., Dragon, F., Kiss, T., Terns R. M., and Terns, M. P. (1999) Nucleolar localization signals of Box H/ACA small nucleolar RNAs. EMBO J. 18:5120-5130. Read Narayanan et al.
• Narayanan, A., Speckmann, W., Terns R. M., and Terns, M. P. (1999) Role of the Box C/D motif in the localization of small nucleolar RNAs to coiled bodies and nucleoli. Molecular Biology of the Cell 10: 2137-2147. Read Narayanan et al.