Daniel R. Schoenberg
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Ph.D. - University of Wisconsin
Post Doctoral - Baylor College of Medicine
Dr. Schoenberg has been selected as director of the newly created Center for RNA Biology.
The Schoenberg lab studies the post-transcriptional control of gene expression through changes in mRNA translation and decay. These concepts are addressed in project areas which study an enzyme that selectively targets the decay of a specific group of mRNAs, the function of this enzyme to the degradation of a defective form of beta-globin mRNA in erythroid cells, and the relationship between the cap structure, mRNA silencing and the re-activation of silenced mRNAs.
Endonuclease-mediated mRNA decay
Gene expression is ultimately determined by the translation of a given mRNA. Translation and mRNA decay are closely linked processes, and changes in mRNA decay control the overall expression of large number of genes. For most mRNAs decay begins with shortening of the poly(A) tail, followed by loss of the cap and degradation from both ends of the molecule by exonucleases. We identified an endonuclease termed PMR-1, which instead targets a subset of the transcriptome by binding to specific mRNAs engaged by translating polysomes. The targeting of PMR1 to these mRNAs requires phosphorylation by the oncogenic tyrosine kinase c-Src, and PMR1 appears to be positioned within the cell by direct interaction with the proteins Mena and VASP proteins, which are regulators of the actin cytoskeleton. PMR1 accumulates along the leading edge of the cell of motile cells, and its expression stimulates a 2-fold increase in cell motility. Current work applies proteomics to identify the proteins of the PMR1-containing mRNP, and microarrays and deep sequencing to identify the specific targets of PMR1 with the goal of elucidating the ‘mRNP code’ responsible for directing mRNAs into this novel degradative pathway. Moreover, the stimulation of cellular motility observed upon induction of PMR1 suggests that motility and perhaps the invasive growth of cancer cells may involve localized decay of mRNAs encoding proteins that control this process.
Degradation of defective ß-globin mRNA in erythroid cells
Cooley’s anemia is caused by inheritance of two copies of the ß-globin gene carrying a premature termination codon (PTC) within the body of the mRNA. In most cases a process of mRNA surveillance termed nonsense-mediated mRNA decay (NMD) rapidly degrades such defective mRNAs without the appearance of defined degradation products. However, in erythroid cells PTC-containing beta-globin mRNA is degraded by the PMR1 mRNA endonuclease to generate a defined series of products. Research in progress seeks to determine the relationship between this endonuclease decay process and NMD, and to determine how the detection of a PTC is transduced to activate this endonuclease that is pre-positioned on its target mRNA.
In the course of studying the decay of PTC-containing ß-globin mRNA we examined an earlier report suggesting the 5’ ends of the decay products are modified by a cap or cap-like structure. Addition of the 5’-cap is the first post-transcriptional modification made to newly-synthesized pre-mRNA, and its loss is generally thought to be an irreversible step leading to mRNA decay. We identified a population of capping enzyme in the cytoplasm that can restore the cap onto RNAs that have undergone decapping or lost sequences from their 5’ ends by endonuclease cleavage. This is in a complex with a kinase that converts RNA with a 5’-monophosphate end to a 5’-diphosphate substrate for capping, and we determined that interfering with cytoplasmic capping reduces the ability of cells to recover from stress. Work in progress seeks to identify the uncapped transcriptome in human cells and determine which of these mRNAs are substrates for cytoplasmic capping, and to determine whether cytoplasmic capping is involved in the reactivation of mRNAs that are stored or silenced by microRNAs.
- Nechama M, Peng Y, Bell O, Briata P, Gherzi R, Schoenberg DR and Naveh-Many T (2009) "KSRP-PMR1-exosome association determines parathyroid hormone mRNA levels and stability in transfected cells" BMC Cell Biol. 10(1):70.
- Schoenberg DR and Maquat LE (2009) "Re-capping the message" Trends Biochem Sci. 34(9):435-42.
- Kolb SJ, Sutton S and Schoenberg DR (2009) "RNA processing defects associated with diseases of the motor neuron" Muscle Nerve 41(1):5-17.
- Otsuka Y, Kedersha NL and Schoenberg DR (2009) "Identification of a cytoplasmic complex that adds a cap onto 5'-monophosphate RNA" Mol Cell Biol. 29(8):2155-67.
- Peng Y, Murray EL, Sarkar M, Liu X and Schoenberg DR (2009) "The cytoskeleton-associated Ena/VASP proteins are unanticipated partners of the PMR1 mRNA endonuclease" RNA 15(4):576-87.
- Murray EL and Schoenberg DR (2008) "Assays for determining poly(A) tail length and the polarity of mRNA decay in mammalian cells" Methods Enzymol 448:483-504.
- Otsuka Y and Schoenberg DR (2008) "Approaches for studying PMR1 endonuclease-mediated mRNA decay" Methods Enzymol 448:241-63.
- Jazdzewski K, Murray EL, Franssila K, Jarzab B, Schoenberg DR and de la Chapelle A (2008) "Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma" Proc Natl Acad Sci U S A 105(20):7269-74.
- Murray EL and Schoenberg DR (2008) "Application of the Invader RNA assay to the polarity of vertebrate mRNA decay" Methods Mol Biol 419:259-76.
- Peng J, Murray EL and Schoenberg DR (2008) "In vivo and in vitro analysis of poly(A) length effects on mRNA translation" Methods Mol Biol. 419:215-30.
- Peng Y, Liu X and Schoenberg DR (2008) "The 90-kDa heat shock protein stabilizes the polysomal ribonuclease 1 mRNA endonuclease to degradation by the 26S proteasome" Mol Biol Cell 19(2):546-52.
- Schoenberg DR (2007) “The end defines the means in bacterial mRNA decay” Nat Chem Biol 3(9):535-6.
- Yoon H, He H, Nagy R, Davuluri R, Suster S, Schoenberg D, Pellegata N and de la Chapelle A (2007) “Identification of a novel noncoding RNA gene, NAMA, that is downregulated in papillary thyroid carcinoma with BRAF mutation and associated with growth arrest” Int J Cancer 121(4):767-75.
- Murray EL and Schoenberg DR (2007) "A+U-rich instability elements differentially activate 5'-3' and 3'-5' mRNA" Mol Cell Biol 27(8):2791-9.
- Peng Y and Schoenberg DR (2007) "c-Src activates endonuclease-mediated mRNA decay" Mol Cell 25(5):779-87.
- Yang F, Peng Y, Murray EL, Otsuka Y, Kedersha N and Schoenberg DR (2007) "Polysome-bound endonuclease PMR1 is targeted to stress granules via stress-specific binding to TIA-1" Mol Cell Biol 26(23):8803-13.
- Hartman TR, Qian S, Bolinger C, Fernandez S, Schoenberg DR and Boris-Lawrie K (2006) "RNA helicase A is necessary for translation of selected messenger RNAs" Nat Struct Mol Biol 13(6):509-16.
- Ferraiuolo MA, Basak S, Dostie J, Murray EL, Schoenberg DR and Sonenberg N (2005) "A role for the eIF4E-binding protein 4E-T in p-body formation and mRNA decay" J Cell Biol 170(6):913-24.
- Peng J, Murray EL and Schoenberg DR (2005) "The poly(A)-limiting element enhances mRNA accumulation by increasing the efficiency of pre-mRNA 3' processing" RNA 11(6):958-65.
- Peng J and Schoenberg DR (2005) "RNA with a <20 nt Poly(A) tail imparted by the poly(A)-limiting element is translated as efficiently in vivo as long poly(A) mRNA" RNA 11(7):1131-40.
- Sellers JA, Hou L, Schoenberg DR, Batistuzzo de Medeiros SR, Wahli W and Shelness GS (2005) "Microsomal triglyceride transfer protein promotes the secretion of xenopus laevis vitellogenin A1" J Biol Chem 280(14):13902-5.
- Yang F and Schoenberg DR (2004) "Endonuclease-mediated mRNA decay involves the selective targeting of PMR1 to polyribosome-bound substrate mRNA" Mol Cell 14(4):435-45.
- Yang F, Peng Y and Schoenberg DR (2004) "Endonuclease-mediated mRNA decay requires tyrosine phosphorylation of polysomal ribonuclease 1 (PMR1) for the targeting and degradation of polyribosome-bound substrate mRNA" J Biol Chem 279(47):48993-49002.
- Schoenberg DR ed. (2004) Methods in Molecular Biology Vol. 257 - mRNA Processing and Metabolism: Methods and Protocols, Humana Press, Totowa, NJ.
- Bremer KA, Stevens A and Schoenberg DR (2003) "An endonuclease activity similar to xenopus PMR1 catalyzes the degradation of normal and nonsense-containing human ß-globin mRNA in erythroid cells" RNA 9(9):1157-67.
- Stevens A, Zhang J, Bremer K, Hoepfner R, Wang Y, Antoniou M, Schoenberg DR and Maquat LE (2002) "Human ß-globin mRNA decay in erythroid cells: UG site-preferred endonucleolytic cleavage that is augmented by a premature termination codon" Proc Natl Acad Sci USA 99(20):12741-6.