Distinguished Research Professor Ph.D. (1990) Pennsylvania State University CRISPR: From basic biology to far-reaching biotechnology and biomedical applications. CRISPR-Cas systems are recently discovered RNA-based adaptive immune systems that control invasions of viruses and other mobile genetic elements in prokaryotes (bacteria and archaea). CRISPR-Cas systems function by capturing short invader sequences within the CRISPR locus of the host genome, producing short crRNAs from the CRISPR locus transcripts, and using the crRNAs to guide Cas protein-containing immune effector complexes to recognize and destroy the invading nucleic acids. CRISPR-Cas based immunity is mediated by numerous and diverse Cas proteins and a given organism may possess one or more of the at least 16 distinct sets of known CRISPR-Cas immune modules. We currently know very little about how the key steps in the fascinating CRISPR-Cas immune response pathways occur for most of the systems. Using a powerful combination of molecular, genetic, structural, and biochemical approaches, we are determining the molecular basis for how various CRISPR-Cas systems acquire foreign DNA sequence in their CRISPR locus memory banks to provide heritable immunity against specific invaders. We are also delineating the mechanisms by which diverse crRNA-Cas protein immune effector complexes selectively recognize and destroy foreign nucleic acids as a means to combat the viruses and other transgressors. A comprehensive understanding of how the structurally and functional diverse CRISPR-Cas immune systems each function is essential toward understanding the range of mechanisms that have evolved to protect multitudes of prokaryotes from potentially lethal viral attack. The knowledge gained by our research program will contribute directly to ongoing efforts aimed at exploiting CRISPR-Cas systems as powerful research tools for genome editing and controlled gene expression as well as novel CRISPR-based, sequence-specific antibiotics to selectively combat bacteria and viruses that cause human disease and the spread of antibiotic resistance. Research Research Areas: Molecular Genetics Biotechnology Research Interests: Non-coding RNA function, cancer, and genome defense: biogenesis, trafficking, and function of non-coding RNA-protein complexes; goal to improve understanding and treatment of human disease Selected Publications Selected Publications: Hale, C.R., S. Majumdar, J. Elmore, N. Pfister, M. Compton, S. Olson, A.M. Resch, C.V.C. Glover, B.R. Graveley, R.M. Terns and M.P. Terns. 2012. Essential features and rational design of CRISPR RNAs that function with the Cas RAMP module complex to cleave RNAs. Molecular Cell. Molecular Cell, 45(3):292-302. A.I. Cocozaki, N.F. Ramia, Y. Shao, C.R. Hale, R.M. Terns, M.P. Terns and H. Li. 2012. Structure of the Cmr2 subunit of the CRISPR-Cas RNA silencing complex. Structure. Structure, 20(3):545-553. Zhao Y., E. Abreu, J. Kim, G. Stadler, U. Eskiocak, M.P. Terns, R.M. Terns, J.W. Shay and W.E. Wright. 2011. Processive and distributive extension of human telomeres by telomerase under homeostatic and nonequilibrium conditions. Molecular Cell, 42: 297-307. Terns, M.P. and R.M. Terns. 2011. CRISPR-based adaptive immune systems. Current Opinion in Microbiology, 14: 321-7. Abreu E., R.M. Terns and M.P. Terns. 2011. Visualization of human telomerase localization by fluorescence microscopy techniques. Methods in Mol Biol., 735: 125-37. Wang R., G. Preamplume, M.P. Terns, R.M. Terns and H. Li. 2011. Interaction of the Cas6 riboendonuclease with CRISPR RNAs: Recognition and cleavage. Structure 19: 257-64. Carte J., N.T. Pfister, M.M. Compton, R.M. Terns and M.P. Terns. 2010. Binding and cleavage of CRISPR RNA by Cas6. RNA 16: 2181-8. Xue S., R. Wang, F. Yang, R.M. Terns, M.P. Terns, X. Zhang, E.S. Maxwell and H. Li. 2010. Structural basis for substrate placement by an archaeal box C/D ribonucleoprotein particle. Molecular Cell 39: 939-49. Tomlinson, R.L., J. Li, B.R. Culp, R.M. Terns and M.P. Terns. 2010. A Cajal body-independent pathway for telomerase trafficking in mice. Experimental Cell Research 316: 2797-809. Abreu, E., E. Aritonovska, P. Reichenbach, G. Cristofari, B. Culp, R.M. Terns, J. Lingner and M.P. Terns. 2010. TIN2-tethered TPP1 recruits human telomerase to telomeres in vivo. Molecular and Cellular Biology 30: 2971-82. Li, Z.H., R. Tomlinson, R.M. Terns and M.P. Terns. 2010. Telomerase Trafficking and Assembly in Xenopus Oocytes. Journal of Cell Science 123: 2464-72. Hale C.R., P. Zhao, S. Olson, M.O. Duff, B.R. Graveley, L. Wells, R.M. Terns and M.P. Terns. 2009. RNA-Guided RNA Cleavage by a CRISPR RNA-Cas Protein Complex. Cell 139: 945-56. Liang, B., J. Zhou, E. Kahen, R.M. Terns, M.P. Terns and H. Li. 2009. Structure of a functional ribonucleoprotein pseudouridine synthase bound to a substrate RNA. Nature Structural and Molecular Biology 16: 740-746. Venteicher, A.S., E.A. Abreu, Z. Meng, K.E. McCann, R.M. Terns, T.D. Veenstra, M.P. Terns and S.E. Artandi. 2009. A telomerase holoenzyme protein required for Cajal body localization and telomere synthesis. Science 323: 644-648. Carte, J., R. Wang, H. Li, R.M. Terns and M.P. Terns. 2008. Cas6 is an endoribonuclease that generates guide RNAs for invader defense in prokaryotes. Genes & Development 22: 3489-3496. Hale, C., K. Kleppe, R.M. Terns and M.P. Terns. 2008. Prokaryotic silencing (psi)RNAs in Pyrococcus furiosus. RNA 14: 2572-2579. Tomlinson, R., E. Abreu, T. Ziegler, H. Ly, C. Counter, R.M. Terns and M.P. Terns. 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: 3793-3800. Baker, D.L., N.T. Seyfried, H. Li, R. Orlando, R.M. Terns and M.P. Terns. 2008. Determination of protein-RNA interaction sites in the Cbf5-H/ACA guide RNA complex by mass spectrometric protein footprinting. Biochemistry 6: 1500-1510. Qiu, H., J. Eifert, L. Wacheul, M. Thiry, A.C. Berger, J.L. Woolford, A.H. Corbett, D.L.J. Lafontaine, R.M. Terns and M.P. Terns. 2008. Identification of genes that function in the biogenesis and localization of small nucleolar RNAs in Saccharomyces cerevisiae. Molecular & Cellular Biology 28: 3686-3699. Liang, B., S. Xue, R.M. Terns, M.P. Terns and H. Li. 2007. Substrate RNA positioning in the Archaeal H/ACA ribonucleoprotein complex. Nature Structural and Molecular Biology 14: 1189 - 1195. Youssef, O.A., R.M. Terns and M.P. Terns. 2007. Dynamic interactions within sub-complexes of the H/ACA pseudouridylation guide RNP, Nucleic Acids Research 35: 6196-206. Cristofari, G., E. Adolf, P. Reichenbach, K. Sikora, R.M. Terns, M.P. Terns and J. Lingner. 2007. Human telomerase RNA accumulation in Cajal bodies facilitates telomerase recruitment to telomeres and telomere elongation. Molecular Cell 27: 882-889. Oruganti, S., Y. Zhang, H. Robinson, M.P. Terns, R.M. Terns, W. Yang and H. Li. 2007. Alternative conformations of the archaeal Nop56/58-fibrillarin complex imply flexibility in box C/D RNPs. Journal of Molecular Biology 371: 1141-50. Matera, A.G., M.P. Terns and R.M. Terns. 2007. Noncoding RNAs: Lessons from the snRNAs and snoRNAs. Nature Reviews Molecular Cell Biology 8: 209-20. Terns, M.P. and R.M. Terns. 2006. Non-Coding RNAs of the H/ACA Family. 71st Cold Spring Harbor Laboratory Symposium on Quantitative Biology: Regulatory RNAs 71: 395-405. Roovers, M., C. Hale, C. Tricot, M.P. Terns, R.M. Terns, H. Grosjean and L. Droogmans. 2006. Formation of the conserved pseudouridine at position 55 in archaeal tRNA. Nucleic Acids Research 34: 4293-301. Rashid, R., B. Liang, D.L. Baker, O.A. Youssef, Y. He, K. Phipps, R.M. Terns, M.P. Terns and H. Li. 2006. Crystal structure of a Cbf5-Nop10-Gar1 complex and implications in RNA-guided pseudouridylation and dyskeratosis congenita. Molecular Cell 21: 249-60. Tomlinson, R.L., T.D. Ziegler, T. Supakorndej, R.M. Terns, and M.P. Terns. 2005. Cell cycle regulated trafficking of human telomerase to telomeres. Molecular Biology of the Cell 17: 955-65. Baker, D.L., O.A. Youssef, M.I.R. Chastkofsky, D. Dy, R.M. Terns and M.P. Terns. 2005. RNA-Guided RNA modification: Functional organization of the Archaeal H/ACA RNP. Genes & Development 19: 1238-48. Starostina, N.G., S. Marshburn, L.S. Johnson, S.R. Eddy, R.M. Terns and M.P. Terns. 2004. Circular box C/D RNAs in Pyrococcus furiosus. Proceedings of the National Academy of Sciences 101: 14097-101. Zhu, Y., R. Tomlinson, A. Lukowiak, R. M. Terns and M.P. Terns. 2003. Telomerase RNA accumulates in Cajal bodies in human cancer cells. Molecular Biology of the Cell 15: 81-90. Leary, D. J., M. P. Terns and S. Huang. 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: 281-93. Terns, M.P. and R.M. Terns. 2002. Small nucleolar RNAs: Versatile Trans-acting molecules of ancient evolutionary origin. Gene Expression 10: 17-39. Speckmann, W., Z-H. Li, T. Lowe, S. Eddy, R.M. Terns, and M.P. Terns. 2002. Archaeal guide RNAs function in rRNA modification in the eukaryotic nucleus. Current Biology 12: 199-203. Etheridge K.T., S.S. Banik, B.N. Armbruster, Y. Zhu, R.M. Terns, M.P. Terns and C.M. Counter. 2002. The nucleolar localization domain of the catalytic subunit of human telomerase. Journal of Biological Chemistry 277: 24764-70. Cahill, N.M., K. Friend, W. Speckmann, Z.H. Li, R.M. Terns, M.P. Terns and J.A. Steitz. 2002. Site-specific cross-linking analyses reveal an asymmetric protein distribution for a box C/D snoRNP. EMBO Journal 21: 3816-3628. Narayanan, A., J. Eifert, K.A. Marfatia, I.G. Macara, A.H Corbett, R.M. Terns and M.P. Terns. 2002. Nuclear RanGTP is not required for targeting small nucleolar RNAs to the nucleolus. Journal of Cell Science 116: 177-186. Whitehead, S.E., K.W. Jones, X. Zhang, X. Cheng , R.M. Terns and M.P. Terns. 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: 48087-93. Zhao, X., Z-H. Li, R.M. Terns, M.P. Terns, and Y.-T. Yu 2002. An H/ACA guide RNA directs U2 pseudouridylation at two different sites in the branch point recognition region in Xenopus oocytes. RNA 8: 1515-25. Yu, Y., M. Shu, A. Narayanan, R.M. Terns, M.P. Terns and J.A. Steitz. 2001. Internal modification of U2 snRNA occurs in nucleoli of Xenopus oocytes. Journal of Cell Biology 152: 1279-1288. Jones, K.W., K. Gorzynski, C.M. Hales, U. Fischer, F. Badbanchi, R. M. Terns and M.P. Terns. 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. Terns, M.P. and R.M. Terns. 2001. Macromolecular complexes: SMN - the master assembler. Current Biology 11: R862–R864. Lukowiak, A. A., A. Narayanan, Z. Li, R.M. Terns and M.P. Terns. 2001. The snoRNA domain of human telomerase RNA functions to localize the RNA within the nucleus. RNA 7: 1833-1844. Lukowiak, A., S. Granneman, S. Mattox, W. Speckmann, K. Jones, H. Pluk, W. van Venrooij, R.M. Terns and M.P. Terns. 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. Speckmann, W., R.M. Terns and M.P. Terns. 2000. The Box C/D motif targets 5' cap hypermethylation of small nucleolar RNAs. Nucleic Acids Research 28: 4467-4473. Narayanan, A., W.Speckmann, R.M. Terns and M.P. Terns. 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. Narayanan, A., A. Lukowiak , B. Jady, F. Dragon, T. Kiss, R.M. Terns and M.P. Terns. 1999. Nucleolar localization signals of Box H/ACA small nucleolar RNAs. EMBO J. 18: 5120-5130. Speckmann, W., A. Narayanan, R.M. Terns and M.P. Terns. 1999. Nuclear retention elements of U3 small nucleolar RNA. Mol. Cell. Biol. 19: 8412-8421. Terns, M.P., C. Grimm, E. Lund and J.E. Dahlberg. 1995. A common maturation pathway for small nucleolar RNAs. EMBO J. 14: 4860-4871. Terns, M.P. and J.E. Dahlberg. 1994. Retention and 5' cap trimethylation of U3 snRNA in the nucleus. Science 264: 959-961.
