
The Cellular Functions of RNA Nucleases
Wednesday, November 2, 2011
The ability to cleave nucleic acids is an essential activity for a wide array of cellular processes. Whether it is maintaining quality control of cellular mRNA or the generation of non coding RNAs, nucleases are fundamental components central to proper cell function. In this one-day forum, speakers will discuss the diverse roles that cellular nucleases perform in the biogenesis and/or quality control of rRNAs, mRNAs, and miRNAs. The forum will also focus on unique and common structural features shared between different nucleases and the diseases associated with nuclease malfunction. The overall objective of this event is to explore the current understanding of nucleases as they relate to a diverse array of cellular functions.
Networking Reception to Follow.
Registration Pricing
Member | $25 |
Student / Postdoc / Fellow Member | $10 |
Student / Postdoc / Fellow Nonmember | $40 |
Nonmember Academic | $60 |
Nonmember Not for Profit | $60 |
Nonmember Corporate | $80 |
Agenda
* Presentation times are subject to change
Wednesday, November 2, 2011 | |
8:00 am | Registration and Breakfast |
9:00 am | Opening Remarks |
Introduction to Nucleases | |
9:15 am | Conserved Function and Expression Profiles of RNA Nucleases |
Session I: Nucleases in rRNA Biogenesis | |
9:30 am | Structure and Mechanism of RNA 3’ Cyclase and the 18S rRNA Processosome Component Rcl1 |
10:00 am | Utp24 in the Biogenesis of 18s rRNA |
10:30 am | Coffee Break |
Session II: Nucleases in miRNA Biogenesis | |
11:00 am | Non-canonical miRNA Biogenesis |
11:30 am | Diverse Endonucleolytic Cleavage Sites in the Mammalian Transcriptome Depend Upon microRNAs, Drosha, and Additional Nucleases |
12:00 pm | A Role for Non-canonical microRNAs as Revealed by Rhenotypic Differences Between Dgcr8 and Dicer Knockouts |
12:30 pm | Cytoplasmic Processing of Primary Viral microRNAs |
1:00 pm | Lunch |
Session III: Nuclease Structures | |
2:00 pm | Structures of Human Exonuclease-I DNA Complexes Reveal a Unified Understanding of 5′ Structure Specific Repair Nucleases |
2:30 pm | RNA Decay Activities of the Eukaryotic RNA Exosome |
3:00 pm | Coffee Break |
3:30 pm | Structure and Nuclease Activity of C3PO |
4:00 pm | 5’-3’ Exoribonucleases, RNA Degradation and Quality Control |
Session IV: Nucleases in Disease | |
4:30 pm | The Role of Dicer in Age-related Macular Degeneration |
1-hour reception to follow |
Speakers
Organizers
Eric Lai, PhD
Memorial Sloan Kettering Cancer Center
Eric Lai's interest in developmental biology began at Harvard, where he studied the C. elegans homeoprotein Ceh-20 for his BA. thesis with Gary Ruvkun. He did his PhD with James Posakony at UC San Diego, where he characterized a new family of Notch pathway components in Drosophila, and the repression of Notch target genes by novel 3′ UTR sequence motifs. He continued to study the mechanism of Notch signaling as a postdoc with Gerald Rubin at UC Berkeley, but shifted his focus to small RNAs upon realizing that the post-transcriptional regulatory motifs he studied earlier were in fact microRNA binding sites. In 2005, Dr. Lai joined the Developmental Biology faculty at Sloan Kettering Institute in New York City.
Eric Lai's lab currently studies two general topics: (1) the biogenesis and biological activities of small regulatory RNAs, including microRNAs (miRNAs), small interfering RNAs (siRNAs) and piwi-interacting RNAs (piRNAs), and (2) the determination of cell fates via cell–cell signaling mediated by the Notch pathway. His group combines biochemical, genetic, and computational strategies towards understanding gene regulation at transcriptional and post-transcriptional levels. They have had particular interest in studying how these regulatory mechanisms direct the intricate patterning of Drosophila nervous system, and more recently, the self-renewal and differentiation of mammalian neural stem cells.
Benjamin R. tenOever, PhD
Mount Sinai School of Medicine
Dr. tenOever completed his postdoctoral formation in Molecular Biology from Harvard University in 2007 after receiving his PhD in Virology from McGill University in 2004. In August of 2007, Dr. tenOever joined Mount Sinai School of Medicine and is presently an Associate Professor of Microbiology. His work focuses on the molecular interactions between viruses and their host. More specifically, the lab studies the host transcriptional response to infection and the means by which the virus circumvents these activities to propagate the infection. This research encompasses the study of cellular antiviral proteins and small RNAs, of both cellular and virus origin, which contribute to the outcome of infection. The overall objective of this lab is to gain an understanding of the molecular basis of virus pathogenicity in an effort to generate improved therapeutics. Dr. tenOever is both a Pew scholar and a Burroughs Wellcome investigator and the recipient of a number of prestigious honors including young investigator awards from the American Society of Microbiology, the National Academy of Sciences, and the White House.
Thomas Tuschl, PhD
The Rockefeller University
Dr. Tuschl received his PhD in chemistry from the University of Regensburg, in Germany, in 1995. He went to the Max Planck Institute for Experimental Medicine in Göttingen, Germany, pursuing research with Fritz Eckstein. He next joined the biology department at the Massachusetts Institute of Technology and the Whitehead Institute for Biomedical Research, where he worked with Phillip A. Sharp and David P. Bartel. Dr. Tuschl was a junior investigator at the Max Planck Institute for Biophysical Chemistry before coming to Rockefeller in 2003 as associate professor. He was named professor in 2009. Dr. Tuschl’s most recent honors include the Ernst Jung Prize for Medicine in 2008 and the Max Delbrück Medal and the Karl Heinz Beckurtz Award in 2007. In 2006 he received the Molecular Bioanalytics Prize from Roche Diagnostics. In 2005 he was named a fellow of the New York Academy of Sciences and received the Meyenburg Prize, the Irma T. Hirschl Trust Career Scientist Award and the Ernst Schering Award. In 2003 he received the Wiley Prize in Biomedical Sciences, the New York City Mayor’s Award for Excellence in Science and Technology and the Newcomb Cleveland Prize from the American Association for the Advancement of Science. Dr. Tuschl was the recipient of the European Molecular Biology Organization Young Investigator Award in 2001 and the Biofuture Award from the German government in 1999. He is also a Howard Hughes Medical Institute investigator.
Jennifer Henry, PhD
The New York Academy of Sciences
Marta Murcia, PhD
The New York Academy of Sciences
Speakers
Jayakrishna Ambati, MD
University of Kentucky
Jayakrishna Ambati, MD is Professor of Physiology and Professor & Vice-Chair of Ophthalmology and Visual Sciences at the University of Kentucky. He holds the Dr. E. Vernon Smith & Eloise C. Smith Endowed Chair in Macular Degeneration Research. His laboratory has revealed novel mechanisms of age-related macular degeneration and angiogenesis. He is the 2010 ARVO Cogan Awardee and the winner of the 2010 Roger H. Johnson Memorial Award for Macular Degeneration Research. He is the first ophthalmologist to win the Doris Duke Distinguished Clinical Scientist Award and the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research. Research to Prevent Blindness has awarded him its Senior Scientific Investigator Award, Lew R. Wasserman Merit Award, and Physician-Scientist Award. He was elected to The American Society for Clinical Investigation and was the first ophthalmologist to be elected to The Association of American Physicians. He serves on the Editorial Board of Investigative Ophthalmology & Visual Science and is an Associate Editor of Ophthalmology.
Susan J. Baserga, MD, PhD
Yale University
Susan J. Baserga is a Professor at Yale University with a primary appointment in Molecular Biophysics & Biochemistry and joint appointments in the Departments of Genetics and Therapeutic Radiology. Susan Baserga received a BS in Biology from Yale College and an MD and PhD (Human Genetics) from Yale in 1988. The focus of Susan's research is on the function of ribonucleoproteins in pre-rRNA processing and pre-ribosome assembly. Her laboratory website is http://info.med.yale.edu/mbb/baserga/.
Lorena Beese, PhD
Duke University School of Medicine
Lorena S. Beese, PhD, is a James B. Duke Professor in the Department of Biochemistry, at Duke University Medical Center. She earned a B.A. degree in mathematics and biology from Oberlin College and a Ph.D. in Biophysics from Brandeis University. Dr. Beese completed postdoctoral training at Yale University in the Department of Molecular Biophysics and Biochemistry under the direction of Dr. Thomas A. Steitz. She joined the Duke faculty in 1992 and has served as Co-director for the Structural and Chemical Biology Program in the Duke Comprehensive Cancer Center, Director of Graduate Studies for the Structural Biology and Biophysics Program, and Director of the Center for Structural Biology. Dr. Beese’s research focuses on understanding the molecular mechanisms that underlie DNA replication and human mismatch repair. She has carried out pioneering work that elucidated the structure and mechanism of protein prenyltransferases, enzymes that catalyze essential post-translational modifications to cell-signaling molecules. Additionally, she has contributed to development of therapeutics for treatment of cancer and infectious disease. Dr. Beese was elected to the National Academy of Sciences in 2009. Other honors include a Searle Scholar Award, a MERIT Award from the National Institutes of Health.
Robert Blelloch, MD, PhD
University of California, San Francisco
Dr. Robert Blelloch is an Associate Professor at University of California – San Francisco. He is a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, the Center of Reproductive Sciences, and the Diller Cancer Center. He holds appointments in the Departments of Urology, Obstetrics/Gynecology, and Pathology. He is clinically trained in Clinical Pathology and Transfusion Medicine. His research interests are in the epigenetic regulation of stem cells and cancer. His major focus in the past few years has been on the role of non-coding small RNAs, microRNAs and endo-siRNAs, in regulating embryonic stem cell self-renewal and differentiation. He is currently expanding these efforts into somatic stem cells and cancer. He has expertise in genetics, genomics, epigenetics, small RNAs, stem cell biology, embryology, and cancer.
Stefanie Gerstberger
The Rockefeller University
Stefanie Gerstberger is a graduate student within the Tri-Institutional Chemical Biology program of The Rockefeller University, Memorial Sloan-Kettering Cancer Research Center and Weill Cornell Medical School, and a member of the Tuschl laboratory. She studied Biochemistry and Chemistry at Oxford University and received her MChem degree in 2009.
Fedor V. Karginov, PhD
Cold Spring Harbor Laboratory
Fedor Karginov received a BS degree in chemistry from University of Virginia, Charlottesville, VA. He underwent graduate studies to earn a PhD in chemistry and biochemistry at the University of Colorado in Boulder, CO, in the laboratory of Olke Uhlenbeck, where he studied the modular structure and enzymology of RNA helicases. Fedor went on to a postdoctoral position at Cold Spring Harbor Laboratory in the group of Gregory Hannon. His research focus and interests include mammalian microRNA biology, roles and mechanisms of Argonaute proteins, and identification of microRNA targets.
Christopher D. Lima, PhD
Memorial Sloan Kettering Cancer Center
Christopher D. Lima is a Professor and Member in the Structural Biology Program at the Memorial Sloan-Kettering Cancer Center in New York City. He received his PhD in 1994 from Northwestern University for his work on E. coli topoisomerase I under the supervision of Dr. Alfonso Mondragon. After completing his postdoctoral studies as a Helen Hay Whitney Fellow at Columbia University under the supervision of Dr. Wayne A. Hendrickson he joined the faculty at the Weill Medical College of Cornell University in 1998. He moved his laboratory to the Sloan-Kettering Institute in 2003. Dr. Lima received the Louise and Allston Boyer Young Investigator Award, the Mayor's Award for Excellence in Science and Technology, the Beckman Young Investigator Award, and the Rita Allen Scholar Award. Since starting his lab, Dr. Lima's research has focused on pathways that contribute to RNA processing, 5′ cap formation, and RNA decay and on mechanisms that underlie post-translational protein modification by the ubiquitin-like modifier SUMO.
Dinshaw J. Patel, PhD
Memorial Sloan Kettering Cancer Center
Stewart Shuman, MD, PhD
Memorial Sloan Kettering Cancer Center
Liang Tong, PhD
Columbia University
Liang Tong received his B. Sc. degree in chemistry from Peking University in China, and his PhD in protein crystallography from the University of California at Berkeley, working in the laboratory of Sung-Hou Kim. He was a post-doctoral fellow in the laboratory of Michael Rossmann at Purdue University in West Lafayette, IN. He then established a structure-based drug design laboratory at Boehringer Ingelheim Pharmaceuticals, Inc. in Ridgefield, CT. He joined the faculty at Columbia University in 1997 and is now Professor of Biological Sciences. His current research interests include enzymes involved in RNA degradation and quality control, proteins involved in pre-mRNA 3′-end processing, as well as enzymes involved in fatty acid metabolism.
Abstracts
Introduction to Nucleases
Conserved Function and Expression Profiles of RNA Nucleases
Stefanie Gerstberger, The Rockefeller University
Session I: Nucleases in rRNA Biogenesis
Rcl1 in rRNA Processing
Stewart Shuman, MD, PhD, Memorial Sloan Kettering Cancer Center
Eukaryal Rcl1 is an essential nucleolar protein required for U3 snoRNA-guided pre-rRNA processing at sites flanking the 18S rRNA sequence. A potential catalytic role for Rcl1 during pre-RNA cleavage has been suggested based on its primary structure similarity to RNA 3′ cyclase. We've determined the 2.6 Å crystal structure of a biologically active yeast Rcl1, which illuminates its modular 4-domain architecture and overall homology to RNA cyclases, while revealing numerous local differences that account for why Rtcs possess metal-dependent adenylyltransferase activity and Rcls do not. A conserved oxyanion binding site in Rcl1 was highlighted for possible catalytic or RNA binding functions. However, the benign effects of mutations in and around the anion site on Rcl1 activity in vivo militate against such a role.
Utp24 in the Biogenesis of 18s rRNA
Susan J. Baserga, MD, PhD, Yale University
Session II: Nucleases in miRNA Biogenesis
Ago2-mediated miRNA Biogenesis
Eric Lai, PhD, Memorial Sloan Kettering Cancer Center
Diverse Endonucleolytic Cleavage Sites in the Mammalian Transcriptome Depend Upon microRNAs, Drosha, and Additional Nucleases
Fedor V. Karginov, PhD, Cold Spring Harbor Laboratory
A Role for Non-canonical microRNAs as Revealed by Rhenotypic Differences Between Dgcr8 and Dicer Knockouts
Robert H. Blelloch, MD, PhD, University of California, San Francisco
Cytoplasmic Processing of Primary Viral microRNAs
Benjamin R. tenOever, PhD, Mount Sinai School of Medicine
Session III: Nuclease Structures
Structures of Human Exonuclease-I DNA Complexes Reveal a Unified Understanding of 5′ Structure Specific Repair Nucleases
Lorena S. Beese, PhD, Duke University Medical School
1. Orans, J., McSweeney. E.A., Iyer, R.R., Hast, M.A., Hellinga, H.W., Modrich, P, & Beese, L.S. (2011) Structures of human exonuclease 1 DNA complexes suggest a unified mechanism for nuclease family. Cell 145(2): 212-23.
RNA Decay Activities of the Eukaryotic RNA Exosome
Christopher D. Lima, PhD, Memorial Sloan Kettering Cancer Center
Structure and Nuclease Activity of C3PO
Dinshaw J. Patel, PhD, Memorial Sloan Kettering Cancer Center
5′–3′ Exoribonucleases, RNA Degradation and Quality Control
Liang Tong, PhD, Columbia University
The crystal structures of Rat1 (1) and Xrn1 (2) reveal a unique active site landscape for these enzymes and explain their exclusive exonuclease activity. Xrn1 contains four additional domains that are important for nuclease activity and may also be a platform for interacting with other proteins. Unexpectedly, we discovered that the activating protein partner of Rat1, Rai1, is a new eukaryotic enzyme with RNA 5′ pyrophosphohydrolase (PPH) activity (1) as well as decapping activity towards unmethylated 5′ cap (3). We have shown that Rai1 is part of a novel RNA quality surveillance pathway in yeast, promoting the degradation of mRNAs with 5′ capping defects (3).
The presentation will also cover results from our latest research on these important enzymes.
Supported in part by a grant from the NIH.
Session IV: Nucleases in Disease
The Role of Dicer in Macular Degeneration
Jayakrishna Ambati, MD, University of Kentucky
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