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<strong>IN</strong>TRODUCTION T ITLE OF S PECIAL S ECTION In the Forests of RNA Dark Matter RNA S PECIAL S ECTION CREDIT: Y. HAYASHIZAKI AND K. SHIMOKAWA For a long time, RNA has lived in the shadow of its more famous chemical cousin DNA and of the proteins that supposedly took over RNA’s functions in the transition from the “RNA world” to the modern one. The shadow cast has been so deep that a whole universe (or so it seems) of RNA—predominantly of the noncoding variety—has remained hidden from view, until recently. Nor is RNA quite so inert or structurally constrained as its cousin; its conformational versatility and catalytic abilities have been implicated at the very core of protein synthesis and possibly of RNA splicing. Noller (p. 1508) discusses how the basic building block of RNA—the double helix—has been fashioned into the intricate “protein-like” three-dimensional surfaces of the ribosome. A further parallel between RNA and protein is revealed in the structure of an RNA group I self-splicing intron, which uses an arrangement of two metal ions for phosphoryl transfer much like that seen in many protein enzymes (p. 1587). Another group I–like intron catalyzes the formation of a tiny RNA lariat, a reaction strikingly similar to one seen in group II introns and spliceosomal introns (pp. 1584 and 1530). This unusual lariat, at the very 5′ end of the resultant mRNA, is suggested to help protect the mRNA from degradation. The dynamics of the RNA messages passed between nucleus and cytoplasm provide a complex and sophisticated layer of regulation to gene expression, covered by Moore (p. 1514), who describes the teams of proteins that escort and regulate mRNA throughout the various stages of its life (and death). Death for many mRNAs occurs in cytoplasmic foci called P-bodies, which can also act as temporary storage depots for nontranslating mRNAs (see the Science Express Report by M. Brengues et al.). Small noncoding microRNAs (miRNAs) have been found in such abundance that they have been christened the “dark matter” of the cell, a view reinforced by an analysis of the small RNAs found in Arabidopsis (pp. 1567 and 1525). The role of miRNAs and of their close cousins small interfering RNAs (siRNAs) in RNA silencing is discussed by Zamore and Haley (p. 1519), and illustrated in the poster pullout in this issue and in research showing that miRNAs can repress the initiation of translation (p. 1573) and, intriguingly, can also increase mRNA abundance (p. 1577). [See also this week’s online Science of Aging Knowledge Environment (SAGE KE) and Signal Transduction Knowledge Environment (STKE)]. The phrase “dark matter” could well be ascribed to noncoding RNA in general. The discovery that much of the mammalian genome is transcribed, in some places without gaps (so-called transcriptional “forests”), shines a bright light on this embarrassing plentitude: an order of magnitude more transcripts than genes (pp. 1559, 1564, and 1529). Many of these noncoding RNAs (p. 1527) are conserved across species, yet their functions (if any) are largely unknown: A cell-based screen shows one, NRON, to be a regulator of the transcription factor NFAT (p. 1570). Of course, in some cases it is the act of transcription that is the regulatory event, as in the case of the transcriptional regulation of recombination (p. 1581). Finally, even the coding and base-paring capacity of RNA can be altered—by RNA editing, in which bases in the RNA are changed on the fly. Analysis of editing enzymes (p. 1534) reveals that the cell-signaling molecule IP 6 is required for their editing activity. –GUY RIDDIHOUGH CONTENTS R EVIEWS 1508 RNA Structure: Reading the Ribosome H. F. Noller 1514 From Birth to Death: The Complex Lives of Eukaryotic mRNAs M. J. Moore Poster: RNA Silencing 1519 Ribo-gnome: The Big World of Small RNAs P. D. Zamore and B. Haley V IEWPO<strong>IN</strong>TS 1525 It’s a Small RNA World, After All M.W.Vaughn and R. Martienssen 1527 The Functional Genomics of Noncoding RNA J. S. Mattick 1529 Fewer Genes,More Noncoding RNA J.-M. Claverie 1530 Capping by Branching:A New Ribozyme Makes Tiny Lariats A. M. Pyle See also related Science Express Report by M. Brengues et al.; Research Article p. 1534; Reports pp. 1559 to 1590; SAGE KE and STKE material on p. 1451 or at www.sciencemag.org/sciext/rna/ www.sciencemag.org SCIENCE VOL 309 2 SEPTEMBER 2005 1507
RNA S PECIAL S ECTION REVIEW RNA Structure: Reading the Ribosome Harry F. Noller The crystal structures of the ribosome and its subunits have increased the amount of information about RNA structure by about two orders of magnitude. This is leading to an understanding of the principles of RNA folding and of the molecular interactions that underlie the functional capabilities of the ribosome and other RNA systems. Nearly all of the possible types of RNA tertiary interactions have been found in ribosomal RNA. One of these, an abundant tertiary structural motif called the A-minor interaction, has been shown to participate in both aminoacyl-transfer RNA selection and in peptidyl transferase; it may also play an important role in the structural dynamics of the ribosome. As awareness of the biological importance of RNA continues to unfold, the ways in which the structural properties of RNA enable its functional capabilities are becoming all the more interesting. For more than 20 years, our understanding of RNA structure was based almost entirely on the x-ray crystal structure of the 25-kD transfer RNA (tRNA), which appeared in 1974 (1, 2). The widespread lack of success in obtaining useful crystals of other RNA molecules discouraged efforts to solve new structures of more complex RNA molecules. Except for x-ray structures of the smaller hammerhead ribozyme (3, 4)nonew RNA structures of comparable size appeared until the 160-nucleotide (nt) P4-P6 domain of the group I ribozyme, in 1996 (5).Only4years later, the first high-resolution x-ray crystal structures of the ribosomal subunits emerged (6–8), suddenly increasing information on RNA structure by two orders of magnitude (Fig. 1) (9, 10). It is now possible to see directly how RNA can be folded into this breathtakingly intricate and graceful globular 2.5-MD structure containing over 4500 nt and more than 50 proteins, related versions of which are responsible for synthesis of proteins in all cells. The lessons learned from these structures not only address the function and assembly of ribosomes but provide an enormous database for interpreting and predicting the structures of the numerous other cellular RNAs and ribonucleoproteins (RNPs), giving new insights into the structural basis of RNA function as well as how life might have originated in an RNA world (11). and even base triples, that allow it to fold into its unique three-dimensional structure. Inspection of its structure reveals a strong tendency for its strands to follow an A-helical path, even in nonbase-paired regions. For example, hairpin turns are accomplished not by incremental bends in the RNA chain but by abrupt local changes in direction, usually centered around one or two nucleotides. A commonly observed motif is the U turn, seen in the anticodon loop of tRNA, which involves hydrogen bonding of the N3 position of a uridine with the phosphate group of a nucleotide three positions downstream, causing an abrupt reversal in direction of the RNA chain. The tRNA structure also revealed the coaxial stacking of RNA helices: The 7-base-pair (bp) acceptor stem stacks on the 5-bp T stem to form one continuous A-form helical arm of 12 bp (Fig. 2B). The other two helices, the D stem and anticodon stem, also stack, although imperfectly, to form a second helical arm. The two coaxially stacked arms form the familiar L form of tRNA (Fig. 1). Coaxial stacking is a common feature of RNA and is widespread in rRNA, where continuous coaxial stacking of as many as 70 bp is found (Fig. 2). In spite of the wealth of information provided by the 76-nt tRNA, many other common features of RNA structure were absent. The Post-tRNA Renaissance In the absence of new RNA crystals, nuclear magnetic resonance (NMR) spectroscopists began to solve the structures of small RNAs, quickly adding to the diversity of known RNA folding motifs (12). The ability of small ligands to stabilize or rearrange RNA structure was exemplified by the dramatic structural rearrangement of the HIV TAR RNA induced by binding a single arginine residue (13). One of the first rRNA structures obtained by NMR spectroscopy was the sarcin-ricin loop (SRL) of 28S rRNA (14), a structure that interacts with elongation factors EF1 and EF2 and is targeted by the lethal ribotoxins a-sarcin and ricin. The compact 29-nt structure was found to contain several purine-purine base pairs, a tetraloop, and a bulged guanosine adjacent to a reverse Hoogsteen A-U pair. It is stabilized by stacking of bases from opposite strands (termed cross-strand stacking) and H-bonding between imino protons of guanines and phosphate oxygens. The zig-zag fold of its backbone (the S turn), along with its other features, have been identified as recurring motifs in RNA structures. Although NMR spectroscopy sidestepped the difficult problem of crystallizing RNA, it is limited to structural analysis of molecules with an upper size limit of about that of tRNA. This led Lessons from tRNA Many principles of RNA structure were gleaned from the structure of the 76-nt tRNA Phe yeast (1, 2). It showed that RNA forms double-helical structures with Watson-Crick base pairing but also that the presence of ribose in RNA has a profound influence on its structure. tRNA was found to contain many noncanonical base pairs, Center for Molecular Biology of RNA, Department of Molecular, Cell, and Developmental Biology, Sinsheimer Laboratories, University of California, Santa Cruz, Santa Cruz, CA 95064, USA. Fig. 1. The progress of RNA structure determination since 1974, showing the relative sizes of the 76-nt tRNA (1, 2), the 160-nt P4-P6 domain of the group I ribozyme (5), and the 4530-nt 70S ribosome, which also contains more than 50 proteins (31, 32). In the ribosome structure, the 16S, 23S, and 5S rRNAs are colored cyan, gray, and gray-blue, respectively, and the small and large subunit ribosomal proteins are dark blue and magenta, respectively. Two tRNAs (yellow and orange) and a mRNA (green) are visible inside the ribosome. 1508 2 SEPTEMBER 2005 VOL 309 SCIENCE www.sciencemag.org
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2 September 2005 Vol. 309 No. 5740
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SPECIAL ISSUE MAPPING RNA FORM AND
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R EPORTS A Strategy for Probing the
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