Biochemistry

We are interested in understanding the structure, function and evolution of ribonucleoprotein (RNP) complexes in cells. Our attention currently focuses on the telomerase RNP enzyme, a unique reverse transcriptase essential for maintaining telomere length in most eukaryotes. Telomeres act as caps at the ends of chromosomes, and are required for chromosome stability. Telomerase elongates telomere length by adding telomeric repeats to chromosome ends to counterbalance the natural shortening that occurs during DNA replication. Because of its role in chromosome stability, telomerase regulation is a critical step in tumorigenesis and aging. To maintain chromosome stability and infinite growth, telomerase is activated in immortal cells such as stem cells, germ line as well as 90% of human tumors. Moreover, patients with dyskeratosis congenita, a disease of premature aging, carry a mutation in the telomerase RNA (TR) or the telomerase reverse transcriptase protein (TERT) genes Elucidation of the molecular mechanism of telomerase function is the main goal of our lab and will have significant medical implications in cancer and aging. Our goals are to understand (1) how telomerase RNP is assembled and regulated in cells, (2) how different components of the complex participate in the regulation of telomerase function, and (3) how this RNP complex evolved in different eukaryotes. Our research employes a variety of approaches involving biochemical and biophysical techniques, as well as molecular genetics and molecular biology.

Qi, X., D.R. Rand, J.D. Podlevsky, Y. Li, A. Mosig, P.F. Stadler and J.J.-L. Chen (2015) Prevalent and distinct spliceosomal 3'-end processing mechanisms for fungal telomerase RNA. Nature Communications 6, 6105 Stanley, S.E., J.J.-L. Chen, J.D. Podlevsky, J.K. Alder, N.N. Hansel, R. Mathias, X. Qi, N.N. Rafaels, R.A. Wise, E.K. Silverman, K.C. Barnes and M. Armanios (2014) Telomerase mutations in smokers with emphysema. The Journal of Clinical Investigation 125(2), 563-70 Brown, A.F., J.D. Podlevsky, X. Qi, Y. Chen, M. Xie, and J.J.-L. Chen (2014) A self-regulating template in human telomerase. Proc. Natl. Acad. Sci. U.S.A. 111(31): 11311-11316 Huang, J., A.F. Brown, J. Wu, J. Xue, C.J. Bley, D.P. Rand, L. Wu, R. Zhang, J.J.-L. Chen* and M. Lei* (2014) Structural basis for protein-RNA recognition in telomerase. Nature Structural and Molecular Biology 21:507-512 Brown, A.F., J.D. Podlevsky and J.J.-L. Chen (2014) Telomerase: A eukaryotic DNA polymerase specialized in telomeric repeat synthesis. In Nucleic Acid Polymerases-1st edition, M. Trakselis and K. Murakami, eds., Springer Press. p.215-236. Li, Y., J.D. Podlevsky, M. Marz, X. Qi, S. Hoffmann, P.F. Stadler and J.J.-L. Chen (2013) Identification of purple sea urchin telomerase RNA using a next-generation sequencing based approach. RNA 19(6): 852-860 Gramatges, M.M., X. Qi, G.S. Sasa, J.J.-L. Chen and A.A. Bertuch (2013) A homozygous telomerase T motif variant resulting in markedly reduced repeat addition processivity in siblings with Hoyeraal Hreidarsson syndrome. Blood 121(18):3586-3593 Qi, X., Y. Li, S. Honda, S. Hoffmann, M. Marz. A. Mosig, J.D. Podlevsky, P.F. Stadler, E. Selker and J.J.-L. Chen (2012) The common ancestral core of vertebrate and fungal telomerase RNAs. Nucleic Acids Research 41(1): 450-462 Qi, X., M. Xie, A.F. Brown, C.J. Bley, J.D. Podlevsky and J.J.-L. Chen (2012) RNA/DNA hybrid binding affinity determines telomerase template translocation efficiency. EMBO J. 31: 150-161 Tzfati, Y. and J.J.-L. Chen (2012) Telomerase RNA: Structure, function, and molecular mechanisms. In Telomerases: Chemistry, Biology and Clinical Applications-1st edition, N. Lue and C. Autexier, eds., John Wiley & Sons, Inc. p.23-51. Podlevsky, J.D. and J.J.-L. Chen (2012) It all comes together at the ends: Structure, function, and biogenesis of telomerase. Mutation Research 730: 3-11 Bley, C.J., X. Qi, D.P. Rand, C.R. Borges, R.W. Nelson and J.J.-L. Chen (2011) RNA-protein binding interface in the telomerase ribonucleoprotein. Proc. Natl. Acad. Sci. U.S.A. 108(51): 20333-20338 Parry, E.M., J.K. Alder, X. Qi, J.J.-L. Chen and M.Y. Armanios (2011) Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood 117(21): 5607-5611 Alder, J.K., J.D. Cogan, A.F. Brown, C.J. Anderson, W.E. Lawson, P.M. Lansdorp, J.A. Phillips 3rd, J.E. Loyd, J.J.-L. Chen, and M.Y. Armanios (2011) Ancestral mutation in telomerase causes defects in repeat addition processivity and manifests as familial pulmonary fibrosis. PLoS Genetics 7(3): e1001352 Lawrence, R.M., B. Varco-Merth, C.J. Bley, J.J.-L. Chen, and P. Fromme (2011) Recombinant production and purification of the subunit c of chloroplast ATP synthase. Protein Expression and Purification 76: 15-24. Xie, M., J.D. Podlevsky, X. Qi, C.J. Bley and J.J.-L. Chen (2010) A novel motif in telomerase reverse transcriptase regulates telomere repeat addition rate and processivity. Nucleic Acids Research 38: 1982-1996 Stadler,P.F., J.J.-L. Chen, J. Hackermuller, S. Hoffmann, P. Khaitovich, A. Kretzschmar, A. Mosig, S.J. Prohaska, X. Qi, K. Schutt and K. Ullmann (2009) Evolution of vault RNAs. Molecular Biology and Evolution 26: 1975-1991. Alder, J.K., J.J.-L Chen, L. Lancaster, S. Danoff, S.C. Su, M. Prince, I. Vulto, M. Xie, X. Qi, R.M. Tuder, J.A. Phillips, P.M. Lansdorp, J.E. Loyd and M.Y. Armanios (2008) Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc. Natl. Acad. Sci. U.S.A. 105: 13051-13056 Ye, Y., W. Wen, Y. Xiang, X. Qi, J.T. LaBelle, J.J.-L. Chen and J. Wang (2008) Direct electrochemical monitoring of RNase activity. Electroanalysis 20: 919-922. Xie, M., A. Mosig, X. Qi, Y. Li, P.F. Stadler and J.J.-L. Chen (2008) Structure and function of the smallest vertebrate telomerase RNA from teleost fish. Journal of Biological Chemistry 283: 2049-2059

Podlevsky, J.D., C.J. Bley, R.V. Omana, X. Qi and J.J.-L. Chen (2008) The telomerase database. Nucleic Acids Research 36: D339-D343