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Making and Breaking the Message University of Massachusetts Medical School eScholarship@UMMS Open Access Articles Open Access Publications by UMMS Authors 2003-11-13 Making and breaking the message David A. Mangus University of Massachusetts Medical School Et al. Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/oapubs Part of the Microbiology Commons, and the Molecular Genetics Commons Repository Citation Mangus DA, van Hoof A. (2003). Making and breaking the message. Open Access Articles. https://doi.org/10.1186/gb-2003-4-11-346. Retrieved from https://escholarship.umassmed.edu/oapubs/ 608 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in Open Access Articles by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. Meeting report Making and breaking the message comment David A Mangus* and Ambro van Hoof† Addresses: *Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA. †Department of Microbiology and Molecular Genetics, University of Texas Health Sciences Center, 6431 Fannin JFB 1.700, Houston, TX 77030, USA. Correspondence: David A Mangus. E-mail: [email protected] reviews Published: 21 October 2003 Genome Biology 2003, 4:346 The electronic version of this article is the complete one and can be found online at http://genomebiology.com/2003/4/11/346 © 2003 BioMed Central Ltd reports Thomas Walz (Harvard Medical School, Boston, USA) all A report on the Cold Spring Harbor Laboratory meeting indicate that the active spliceosome (C complex) has three ‘Eukaryotic mRNA Processing’, Cold Spring Harbor, USA, 20- domains of density surrounding a central cavity. The spliceo- 24 August 2003. some structures are roughly 270 × 250 × 240 Å in size, with resolutions ranging between 20 Å and 40 Å. The current deposited research challenges are to achieve greater resolution and to locate Amid the Cold Spring Harbor Laboratory celebrations important proteins and RNAs within the structure. We expect marking the 50th anniversary of the elucidation of the struc- that the generation of high-resolution structures of the ture of DNA, researchers gathered to discuss recent spliceosome will be as reinvigorating for research into the advances in understanding the mechanisms regulating gene biochemistry of splicing as the determination of the structure expression. The formation of a functional mRNA from the of the ribosome has been for the study of translation. initial pre-mRNA synthesized by RNA polymerase II requires the addition of a cap and poly(A) tail as well as Because the mechanism of pre-mRNA splicing by the removal of introns. These individual reactions have tradi- spliceosome is very similar to that observed for the group II refereed research tionally been studied in isolation, leading to a perception self-splicing introns, it has been widely postulated that the that they are unconnected. It has, however, become clear catalytic core of the spliceosome would be formed by the that the events that transform a pre-mRNA into an mRNA small nuclear RNAs (snRNAs). James Manley’s group at are often carried out by large ribonucleoprotein (RNP) com- Columbia University (New York, USA) previously reported plexes and that these reactions are coupled and interdepen- that a mixture of three RNA molecules derived from the dent. Interestingly, these events and the links between them spliceosome and intron (U2 and U6 snRNAs and branch- provide quality-control checkpoints to ensure that the point RNA) has catalytic activity that produces an RNA message encoded in the genome is accurately communicated species called ‘RNA X’. This catalytic activity had only interactions to the translation apparatus. These underlying concepts limited similarity to splicing, however. At the conference, framed the presentations we describe below. Saba Valadkhan from the Manley laboratory reported that a different product (RNA Y) is formed when the 5؅ splice site is tethered to the U6 RNA. By several criteria, RNA Y resem- Origins and mechanisms of pre-mRNA splicing bles the product of the first splicing step, in which the The removal of introns from a pre-mRNA is catalyzed by a branchpoint is linked to the 5؅ end of the intron through a large set of RNAs and proteins collectively termed the 2؅-5؅ phosphodiester bond. It therefore appears that the spliceosome. Exciting advances have been made in the visu- spliceosome is indeed a ribozyme. information alization of the spliceosome complexes within the last year. Cryoelectron micrographs presented by Melissa Jurica from Answers to the question of how introns arose during evolu- the laboratory of Melissa Moore (Brandeis University, tion have remained elusive. One long-standing hypothesis is Waltham, USA), Cindy Will from Reinhard Lührmann’s that introns arose very early and facilitated the evolution of group (Max Planck Institute for Biophysical Chemistry, Göt- proteins by exon shuffling. Support for this hypothesis has tingen, Germany), and Melanie Ohi from the laboratory of previously been found in the fact that introns are more Genome Biology 2003, 4:346 346.2 Genome Biology 2003, Volume 4, Issue 11, Article 346 Mangus and van Hoof http://genomebiology.com/2003/4/11/346 frequently found between codons than in the two positions activators can influence recruitment of factors required for that interrupt codons. Richard Padgett (Cleveland Clinic pre-mRNA processing. Foundation, USA) reported that this distribution is true only for the major U2-dependent class of introns, and that a DNA damage leads to a strong but transient block in minor class of U12-dependent introns is less frequently polyadenylation. James Manley’s laboratory had previously found between codons. He suggested that these introns were shown that a BRAC1/BARD1 heterodimer interacts with the .initially more prevalent, but have been unilaterally con- polyadenylation factor CstF and represses 3؅-end formation verted to U2-type introns, and that the current distribution At this meeting, Frida Kleiman from the Manley lab reported of introns should not be used to address the introns-early their further observations that the BRAC1/BARD1 factors versus introns-late conundrum. ubiquitinate the elongating, phosphorylated form of RNA polymerase, RNAP IIO, and that this activity is dependent on the presence of CstF. Collectively, their data suggest that Interdependency of different processes the targeted degradation of RNA polymerase during DNA Several presentations addressed the links between the RNA repair reflects functional interactions between the machiner- .processing events that lead to maturation of mRNA. One of ies for transcription, 3؅-end processing and DNA repair the most dramatic, by Susan Janicki from the laboratory of David Spector (Cold Spring Harbor Laboratory, New York, In yeast, where the number of introns is relatively low, DNA USA), included movies visualizing gene expression in living microarrays have been generated that can distinguish each mammalian cells. Using a reporter gene that allowed simul- unspliced pre-mRNA from its mature mRNA. Todd Burckin taneous localization of the gene, the RNA and the encoded from Grant Hartzog’s lab (University of California Santa protein, as well as various tagged proteins, the group can Cruz, USA) reported on a collaboration between the Hartzog observe the different steps in gene expression. Upon activa- lab and Manuel Ares’ group (also at University of California tion of the gene, RNA polymerase II, splicing factors and Santa Cruz) in which these ‘splicing-sensitive’ arrays were polyadenylation apparatus are all recruited to the site of used to understand better the effects of mRNA-processing transcription and the encoded mRNA accumulates. Simulta- events on splicing by assaying the effects of 70 different neously, heterochromatin proteins leave the transgene locus yeast mutants defective in mRNA synthesis and processing. and the chromatin becomes less compact. Their analysis revealed that defects in mRNA capping or export affect the splicing of many genes. In contrast, muta- As splicing of pre-mRNA can occur co-transcriptionally, it is tions in the carboxy-terminal domain of RNA polymerase II possible that the rate of transcription could influence the affect only some genes, whereas mutants in the cleavage and .selection of 5؅ and/or 3؅ splice sites. Nicole Robson from the polyadenylation machinery have relatively little effect group of Mariano Garcia-Blanco (Duke University, Durham, USA) reported on experiments designed to test this hypothe- Maturation of the 3؅ ends of most pre-mRNAs requires a sis in which they determined the effects of RNA pausing on site-specific cleavage followed by addition of the poly(A) tail. the alternative splicing of the pre-mRNA encoding the The enzyme that synthesizes the tail, poly(A) polymerase, fibroblast growth-factor receptor FGFR2. The team observed was initially characterized and cloned in the early 1990s, that the regulation of alternative splicing of this pre-mRNA but the identity of the factor that mediates the cleavage required active transcription and that the presence of an reaction has remained elusive. In a poster presentation RNA polymerase II pause site promoted inclusion of nearby from Jim Manley’s lab, Kevin Ryan presented preliminary exons. Similarly, Alberto Kornblihtt (University of Buenos data suggesting that the protein CPSF-73
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