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Going for the Code: Regulation of mRNA Processing

Going for the Code
Reported by
Don Monroe

Posted July 26, 2007


The traditional picture of gene expression holds that genetic information in DNA is transcribed into messenger RNA (mRNA), which leaves the nucleus to the cytoplasm, where ribosomes translate its sequence into proteins. Scientists now realize, however, that the real life cycle of mRNA is vastly more complicated.

An April 17, 2007, meeting of the RNAi Discussion Group focused on the life cycle of mRNA and its associated proteins. Even while it is being transcribed, an mRNA is surrounded by proteins—called a messenger ribonucleoprotein complex, or mRNP—which help to determine how it is translated. Some of these proteins respond to specific structures or sequences in the RNA, while others bind to RNA more generally or to other proteins in the complex. This meeting asked what features determine the processing and ultimate fate of various RNAs in such complexes. It also discussed what researchers hypothesize could be an "mRNP code," which may regulate the maturation, transport, stability, and translation of mRNA-containing ribonucleoproteins.

Use the tabs above to see a meeting report and multimedia from this event.

Speakers in this eBriefing:

Scott Tenenbaum (University at Albany)
Georg Stoecklin (German Cancer Research Center)
Markus Landthaler (The Rockefeller University)
Jens Lykke-Andersen (University of Colorado)
Edward Chan (University of Florida)
Carolyn Decker (University of Arizona)
Marianthi Kiriakidou (University of Pennsylvania)
Shobha Vasudevan (Yale University)
Pam Silver (Harvard University)
Matteo Ruggiu (The Rockefeller University)


Journal Articles

Matteo Ruggiu

Jensen KB, Dredge BK, Stefani G, et al. 2000. Nova-1 regulates neuron-specific alternative splicing and is essential for neuronal viability. Neuron 25: 359-371

Licatalosi DD, Darnell RB. 2006. Splicing regulation in neurologic disease. Neuron 52: 93-101.

Ule J, Jensen K, Mele A, Darnell RB. 2005. CLIP: a method for identifying protein-RNA interaction sites in living cells. Methods 37: 376-386.

Ule J, Jensen KB, Ruggiu M, et al. 2003. CLIP identifies Nova-regulated RNA networks in the brain. Science 302: 1212-1215.

Ule J, Stefani G, Mele A, et al. 2006. An RNA map predicting Nova-dependent splicing regulation. Nature 444: 580-586.

Ule J, Ule A, Spencer J, et al. 2005. Nova regulates brain-specific splicing to shape the synapse. Nat. Genet. 37: 844-852.

Pamela Silver

Carroll JS, Liu XS, Brodsky AS, et al. 2005. Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell 122: 33-43. Full Text

Carroll JS, Meyer CA, Song J, et al. 2006. Genome-wide analysis of estrogen receptor binding sites. Nat. Genet. 38: 1289-1297.

Casolari JM, Brown CR, Komili S, et al. 2004. Genome-wide localization of the nuclear transport machinery couples transcriptional status and nuclear organization. Cell 117: 427-439. Full Text

Casolari JM, Brown CR, Drubin DA, et al. 2005. Developmentally induced changes in transcriptional program alter spatial organization across chromosomes. Genes Dev. 19: 1188-1198. Full Text

Drubin DA, Garakani AM, Silver PA. 2006. Motion as a phenotype: the use of live-cell imaging and machine visual screening to characterize transcription-dependent chromosome dynamics. BMC Cell Biol. 7: 19. Full Text

Tsankov AM, Brown CR, Yu MC, et al. 2006. Communication between levels of transcriptional control improves robustness and adaptivity. Mol. Syst. Biol. 2: 65. Full Text

Scott Tenenbaum

George AD, Tenenbaum SA. 2006. MicroRNA modulation of RNA-binding protein regulatory elements. RNA Biol. 3: 57-59.

Keene JD, Tenenbaum SA. 2002. Eukaryotic mRNPs may represent posttranscriptional operons. Mol. Cell 9: 1161-1167. Full Text

Tenenbaum SA, Carson CC, Lager PJ, Keene JD. 2000. Identifying mRNA subsets in messenger ribonucleoprotein complexes by using cDNA arrays. Proc. Natl. Acad. Sci. USA 97: 14085-14090. Full Text

Tenenbaum SA, Lager PJ, Carson CC, Keene JD. 2002. Ribonomics: identifying mRNA subsets in mRNP complexes using antibodies to RNA-binding proteins and genomic arrays. Methods 26: 191-198.

Markus Landthaler

Meister G, Landthaler M, Patkaniowska A, et al. 2004. Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Mol. Cell 15: 185-197. Full Text

Meister G, Landthaler M, Peters L, et al. 2005. Identification of novel argonaute-associated proteins. Curr. Biol. 15: 2149-2155.

Patel DJ, Ma JB, Yuan YR, et al. 2006. Structural biology of RNA silencing and its functional implications. Cold Spring Harb. Symp. Quant. Biol. 71: 81-93.

Peters L, Meister G. 2007. Argonaute proteins: mediators of RNA silencing. Mol. Cell 26: 611-623.

Jens Lykke-Andersen

Anderson P, Kedersha N. 2006. RNA granules. J. Cell Biol. 172: 803-808.

Clement SL, Lykke-Andersen J. 2006. No mercy for messages that mess with the ribosome. Nature Struc. Mol. Biol. 13: 299-301. (PDF, 395 KB) Full Text

Franks TM, Lykke-Andersen J. 2007. TTP and BRF proteins nucleate processing body formation to silence mRNAs with AU-rich elements. Genes Dev. 21: 719-735.

Lykke-Andersen J, Wagner E. 2005. Recruitment and activation of mRNA decay enzymes by two ARE-mediated decay activation domains in the proteins TTP and BRF-1. Genes Dev. 19: 351-361. Full Text

Georg Stoecklin

Newbury SF, Muhlemann O, Stoecklin G. 2006. Turnover in the Alps: an mRNA perspective. Workshops on mechanisms and regulation of mRNA turnover. EMBO Rep. 7: 143-148.

Stoecklin G, Anderson P. 2007. In a tight spot: ARE-mRNAs at processing bodies. Genes Dev. 21: 627-631.

Stoecklin G, Lu M, Rattenbacher B, Moroni C. 2003. A constitutive decay element promotes tumor necrosis factor alpha mRNA degradation via an AU-rich element-independent pathway. Mol. Cell Biol. 23: 3506-3515. Full Text

Stoecklin G, Mayo T, Anderson P. 2006. ARE-mRNA degradation requires the 5′-3′ decay pathway. EMBO Rep. 7: 72-77.

Stoecklin G, Stubbs T, Kedersha N, et al. 2004. MK2-induced tristetraprolin:14-3-3 complexes prevent stress granule association and ARE-mRNA decay. EMBO J. 23: 1313-1324.

Sun L, Stoecklin G, Van Way S, et al. 2007. Tristetraprolin (TTP)-14-3-3 complex formation protects TTP from dephosphorylation by protein phosphatase 2a and stabilizes tumor necrosis factor-α mRNA. J. Biol. Chem. 282: 3766-3777.

Edward Chan

Eystathioy T, Chan EK, Tenenbaum SA, et al. 2002. A phosphorylated cytoplasmic autoantigen, GW182, associates with a unique population of human mRNAs within novel cytoplasmic speckles. Mol. Biol. Cell 13: 1338-51.

Jakymiw A, Ikeda K, Fritzler MJ, et al. 2006. Autoimmune targeting of key components of RNA interference. Arthritis Res. Ther. 8: R87. Full Text

Jakymiw A, Lian S, Eystathioy T, al. 2005. Disruption of GW bodies impairs mammalian RNA interference. Nat. Cell Biol. 7: 1267-1274.

Jakymiw A, Pauley KM, Li S, et al. 2007. The role of GW/P-bodies in RNA processing and silencing. J. Cell Sci. 120: 1317-1323.

Pauley KM, Eystathioy T, Jakymiw A, et al. 2006. Formation of GW bodies is a consequence of miRNA genesis. EMBO Reports 7: 904-910.

Yang Z, Jakymiw A, Wood MR, et al. 2004. GW182 is critical for the stability of GW bodies expressed during the cell cycle and cell proliferation. J. Cell Sci. 117: 5567-5578.

Carolyn Decker

Barbee SA, Estes PS, Cziko A-M, et al. 2006. Staufen- and FMRP-containing neuronal RNPs are structurally and functionally related to somatic P bodies. Neuron 52: 997-1009.

Coller J, Parker R. 2005. General translation repression by activators of decapping. Cell 122: 875-876. Full Text

Parker R & Sheth U. 2007 P-bodies and the control of mRNA translation and degradation. Mol. Cell 25: 635-646.

Teixeira D, Parker R. 2007. Analysis of P-body assembly in Saccharomyces cerevisiae. Mol. Biol. Cell [Epub ahead of print]

Valencia-Sanchez M, Liu J, Hannon GJ, Parker R. 2006. Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 20: 515-524. Full Text

Shobha Vasudevan

Conrad NK, Mili S, Marshall EL, et al. 2006. Identification of a rapid mammalian deadenylation-dependent decay pathway and its inhibition by a viral RNA element. Mol. Cell 24: 943-953.

Fok V, Mitton-Fry RM, Grech A, Steitz JA. 2006. Epstein-Barr virus noncoding RNAs are confined to the nucleus, whereas their partner, the human La protein, undergoes nucleocytoplasmic shuttling. J. Cell Biol. 173: 319-325. Full Text

Hirose T, Ideue T, Nagai M, et al. 2006. A spliceosomal intron binding protein, IBP160, links position-dependent assembly of intron-encoded box C/D snoRNP to pre-mRNA splicing. Mol. Cell 23: 673-684.

Vasudevan S & Steitz JA. 2007. AU-rich-element-mediated upregulation of translation by FXR1 and Argonaute 2. Cell 128: 1105-1118.

Marianthi Kiriakidou

Kiriakidou M, Nelson PT, Kouranov A, et al. 2004. A combined computational-experimental approach predicts human microRNA targets. Genes Dev. 18: 1165-1178. Full Text

Kiriakidou M, Tan GS, Lamprinaki S et al. 2007. An mRNA m(7)G cap binding-like motif within human Ago2 represses translation. Cell 129: 1141-51.

Nelson P, Hatzigeorgiou A, Mourelatos Z. 2004. miRNP:target mRNA association in polyribosomes in a human neuronal cell line. RNA 10: 387-394. Full Text

Nelson P, Kiriakidou M, Sharma A, et al. 2003. The microRNA world: small is mighty. Trends Biochem. Sci. 28: 534-540.


Edward K. L. Chan, PhD

University of Florida
e-mail | web site | publications

Edward Chan is a professor in the Department of Oral Biology at the University of Florida. Chan holds an MSc and Phd from the University of Calgary. He started as a postdoctoral fellow at the Scripps Research Institute and rose to associate professor before he moved his laboratory to the University of Florida.

His laboratory is interested in autoantigens and autoantibodies associated with systemic autoimmune diseases and cancer. Their two main directions are 1) to identify and characterize specific target antigens of human autoantibodies with the focus on understanding why autoantibodies are induced and continually produced in different disease states and, 2) to use human autoantibodies as unique probes to investigate the molecular and cell biology of interesting macromolecules and subcellular organelles which have become autoimmune targets. The overall strategy is that by understanding the biology of autoantigens in health and disease states, they may be able to fully appreciate the functional and pathogenic potentials of autoantibodies.

Carolyn Decker, PhD

The University of Arizona, Howard Hughes Medical Institute
e-mail | web site | publications

Carolyn Decker is a research technician III with the Howard Hughes Medical Institute and the Department of Molecular and Cellular Biology at the University of Arizona. After holding an independent assistant professor position at Washington State University in the Department of Genetics and Cell Biology and the Department of Biochemistry and Biophysics for several years, she returned to the University of Arizona where she is associated with the laboratory of Howard Hughes Investigator, Roy Parker. Her research focuses on understanding the control of translation and degradation of eukaryotic mRNA using budding yeast as a model organism. Decker completed her doctoral work in the Biology/Human Genetics Training Program at Johns Hopkins University.

Marianthi Kiriakidou, MD

University of Pennsylvania
e-mail | web site | publications

Marianthi Kiriakidou is a physician in the Division of Rheumatology at the University of Pennsylvania.

Markus Landthaler, PhD

The Rockefeller University
e-mail | web site | publications

Markus Landthaler is a research associate in the Laboratory of RNA Molecular Biology at the Rockefeller University. He continues the work in Thomas Tuschl's lab that he began as postdoctoral associate in 2003, including studying the biochemistry of the mammalian RNA interference pathway and high-throughput screening for small molecule enhancers and inhibitors of RNA interference. Markus Landthaler was a PhD student at the University at Albany. He was awarded the Irma T. Hirschl Postdoctoral Fellowship in 2005.

Jens Lykke-Andersen, PhD

University of Colorado
e-mail | web site | publications

Jens Lykke-Andersen is a Pew Scholar and an assistant professor in the Department of Molecular, Cellular, and Developmental Biology at the University of Colorado. Lykke-Andersen received his PhD from the Department of Biological Chemistry at the University of Copenhagen. He was a postdoctoral fellow in the laboratory of Jan Christiansen at the University of Copenhagen from 1997 to 1998. He then moved to the laboratory of Joan Steitz at Yale University School of Medicine for postdoctoral work from 1998 to 2001. Lykke-Andersen's lab focuses on dissecting the human cellular mRNA decay machineries.

Matteo Ruggiu, PhD

The Rockefeller University
e-mail | web site | publications

Matteo Ruggiu is a research associate in the laboratory of Robert Darnell at the Rockefeller University. In 1999, Ruggiu received his PhD from the Medical Research Council, Human Genetics Unit in Ediburgh, Scotland. He has been awarded several fellowships, including the Wellbeing Royal College of Obstetricians and Gynaecologists Fellowship and a fellowship from the Human Frontier Science Program Organisation.

Pam Silver, PhD

Harvard Medical School
e-mail | web site | publications

Pamela Silver is a professor in the Department of Systems Biology at Harvard Medical School. She is also the director of the Harvard University Graduate Program in Systems Biology and a member of the Harvard Medical School BBS Graduate Program and the Harvard Biophysics and Chemical Biology Graduate Programs.

Silver received her PhD from the University of California in 1982 and was a postdoctoral fellow in the Department of Biochemistry and Molecular Biology at Harvard University. In 1986, she was appointed to the faculty at Princeton University in the Department of Molecular Biology, and in 1993 she joined the Dana Farber Cancer Institute and Harvard Medical School. She is one of the founding members of the Department of Systems Biology at Harvard Medical School and the first director of the Harvard University PhD Program in Systems Biology.

Georg Stoecklin, MD, PhD

German Cancer Research Center
e-mail | web site | publications

Georg Stoecklin is a group leader in the Helmholtz-University-Junior Research Group for Posttranscriptional Control of Gene Expression at the German Cancer Research Center in Heidelberg, Germany. Stoecklin was a research fellow at the Institute of Medical Microbiology (University of Basel) and in the Division of Rheumatology, Immunology, and Allergy at Brigham and Women's Hospital in Boston, MA. Stoecklin was the recipient of the Paul Basset Prize at the European Cancer Center Meeting, Strasbourg, France, and the 2004 Promoted Speaker Award at the Gordon Research Conference, Andover, NH, USA. The focus of his work is the study of cytokine mRNA turnover.

Scott Tenenbaum, PhD

University at Albany, State University of New York
Gen*NY*Sis Center for Excellence in Cancer Genomics
e-mail | web site | publications

Scott Tenenbaum is an assistant professor of molecular genetics in the Department of Biomedical Sciences at the University at Albany. He received his PhD in microbiology and immunology from Tulane University Medical School. Tenenbaum was trained as a viral immunologist and studied viral-host interactions, focusing on the role of cellular RNA-binding proteins in viral replication. Some of his work resulted in the development of a patented diagnostic for fibromyalgia that is licensed by Autoimmune Technologies. Tenenbaum remained at Tulane for an additional two years after being awarded a Hemophilia Foundation Judith Graham Pool Postdoctoral Fellowship. During this time he studied natural resistance to HIV infection in severe hemophiliacs.

He next worked as a senior postdoctoral fellow with Jack D. Keene at Duke University Medical Center. There he studied RNA-binding proteins eventually developing, along with Craig Carson and Pat Lager, the basic methods for ribonomic profiling, a technology designed for the genomic-scale identification of RNA targets of RNA-binding proteins. This technology is licensed by Ribonomics, a biotechnology start-up company located in the Research Triangle in North Carolina. He joined the University at Albany faculty in 2003 at the Ge*NY*Sis Center for Excellence in Cancer Genomics and continues to expand ribonomic profiling approaches to be used as a method for the genomic-scale identification of RNA-binding protein regulatory elements.

Shobha Vasudevan, PhD

Yale University
e-mail | publications

Shobha Vasudevan is a postdoctoral fellow in the laboratory of Joan Steitz in the Department of Molecular Biophysics and Biochemistry at Yale University. Vasudevan received her PhD from Rutgers University in 2003 and was awarded a Cancer Research Institute (CRI) Postdoctoral Fellowship in 2004. Vasudevan's research focuses on AU-rich element-mediated regulation of translation.

Don Monroe

Don Monroe is a science writer based in Murray Hill, New Jersey. After getting a PhD in physics from MIT, he spent more than fifteen years doing research in physics and electronics technology at Bell Labs. He writes on biology, physics, and technology.