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The catalyst : RNA and the quest to unlock life's deepest secrets
\"One of Literary Hub's Most Anticipated Books of 2024. Exploring the most transformative breakthroughs in biology since the discovery of the double helix, a Nobel Prize-winning scientist unveils the RNA age. For over half a century, DNA has dominated science and the popular imagination as the \"secret of life.\" But over the last several decades, a quiet revolution has taken place. In a series of breathtaking discoveries, the biochemist Thomas R. Cech and a diverse cast of brilliant scientists have revealed that RNA--long overlooked as the passive servant of DNA--sits at the center of biology's greatest mysteries: How did life begin? What makes us human? Why do we get sick and grow old? In The Catalyst, Cech finally brings together years of research to demonstrate that RNA is the true key to understanding life on Earth, from its very origins to our future in the twenty-first century. A gripping journey of discovery, The Catalyst moves from the early experiments that first hinted at RNA's spectacular powers, to Cech's own paradigm-shifting finding that it can catalyze cellular reactions, to the cutting-edge biotechnologies poised to reshape our health. We learn how RNA--once thought merely to transmit DNA's genetic instructions to the cell's protein-making machinery--may have jump-started life itself, and how, at the same time, it can cut our individual lives short through viral diseases and cancer. We see how RNA is implicated in the aging process and explore the darker depths of the supposed fountain of youth, telomerase. And we catch a thrilling glimpse into how RNA-powered therapies--from CRISPR, the revolutionary tool that uses RNA to rewrite the code of life, to the groundbreaking mRNA vaccines that have saved millions during the pandemic, and more--may enable us to improve and even extend life beyond nature's current limits. Written by one of our foremost scientists, The Catalyst is a must-read guide to the present and future of biology and medicine\"-- Provided by publisher.
Book
Drosophila hairpin RNA pathway generates endogenous short interfering RNAs
In contrast to microRNAs and Piwi-associated RNAs, short interfering RNAs (siRNAs) are seemingly dispensable for host-directed gene regulation in Drosophila. This notion is based on the fact that mutants lacking the core siRNA-generating enzyme Dicer-2 or the predominant siRNA effector Argonaute 2 are viable, fertile and of relatively normal morphology. Moreover, endogenous Drosophila siRNAs have not yet been identified. Here we report that siRNAs derived from long hairpin RNA genes (hpRNAs) programme Slicer complexes that can repress endogenous target transcripts. The Drosophila hpRNA pathway is a hybrid mechanism that combines canonical RNA interference factors (Dicer-2, Hen1 (known as CG12367) and Argonaute 2) with a canonical microRNA factor (Loquacious) to generate 21-nucleotide siRNAs. These novel regulatory RNAs reveal unexpected complexity in the sorting of small RNAs, and open a window onto the biological usage of endogenous RNA interference in Drosophila.
Journal Article
Distinct Populations of Primary and Secondary Effectors During RNAi in C. elegans
RNA interference (RNAi) is a phylogenetically widespread gene-silencing process triggered by double-stranded RNA. In plants and Caenorhabditis elegans, two distinct populations of small RNAs have been proposed to participate in RNAi: \"Primary siRNAs\" (derived from DICER nuclease-mediated cleavage of the original trigger) and \"secondary siRNAs\" [additional small RNAs whose synthesis requires an RNA-directed RNA polymerase (RdRP)]. Analyzing small RNAs associated with ongoing RNAi in C. elegans, we found that secondary siRNAs constitute the vast majority. The bulk of secondary siRNAs exhibited structure and sequence indicative of a biosynthetic mode whereby each molecule derives from an independent de novo initiation by RdRP. Analysis of endogenous small RNAs indicated that a fraction derive from a biosynthetic mechanism that is similar to that of secondary siRNAs formed during RNAi, suggesting that small antisense transcripts derived from cellular messenger RNAs by RdRP activity may have key roles in cellular regulation.
Journal Article
Structure of replicating SARS-CoV-2 polymerase
The new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses an RNA-dependent RNA polymerase (RdRp) for the replication of its genome and the transcription of its genes
1
–
3
. Here we present a cryo-electron microscopy structure of the SARS-CoV-2 RdRp in an active form that mimics the replicating enzyme. The structure comprises the viral proteins non-structural protein 12 (nsp12), nsp8 and nsp7, and more than two turns of RNA template–product duplex. The active-site cleft of nsp12 binds to the first turn of RNA and mediates RdRp activity with conserved residues. Two copies of nsp8 bind to opposite sides of the cleft and position the second turn of RNA. Long helical extensions in nsp8 protrude along exiting RNA, forming positively charged ‘sliding poles’. These sliding poles can account for the known processivity of RdRp that is required for replicating the long genome of coronaviruses
3
. Our results enable a detailed analysis of the inhibitory mechanisms that underlie the antiviral activity of substances such as remdesivir, a drug for the treatment of coronavirus disease 2019 (COVID-19)
4
.
A cryo-electron microscopy structure of the RNA-dependent RNA polymerase of SARS-CoV-2 sheds light on coronavirus replication and enables the analysis of the inhibitory mechanisms of candidate antiviral drugs.
Journal Article
Structure of the Dicer-2–R2D2 heterodimer bound to a small RNA duplex
In flies, Argonaute2 (Ago2) and small interfering RNA (siRNA) form an RNA-induced silencing complex to repress viral transcripts
1
. The RNase III enzyme Dicer-2 associates with its partner protein R2D2 and cleaves long double-stranded RNAs to produce 21-nucleotide siRNA duplexes, which are then loaded into Ago2 in a defined orientation
2
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5
. Here we report cryo-electron microscopy structures of the Dicer-2–R2D2 and Dicer-2–R2D2–siRNA complexes. R2D2 interacts with the helicase domain and the central linker of Dicer-2 to inhibit the promiscuous processing of microRNA precursors by Dicer-2. Notably, our structure represents the strand-selection state in the siRNA-loading process, and reveals that R2D2 asymmetrically recognizes the end of the siRNA duplex with the higher base-pairing stability, and the other end is exposed to the solvent and is accessible by Ago2. Our findings explain how R2D2 senses the thermodynamic asymmetry of the siRNA and facilitates the siRNA loading into Ago2 in a defined orientation, thereby determining which strand of the siRNA duplex is used by Ago2 as the guide strand for target silencing.
Cryo-electron microscopy structures of
Drosophila
Dicer-2–R2D2 complexes with and without small interfering RNA reveal how the RNA is presented to Argonaute in the correct orientation for viral gene silencing.
Journal Article
Phloem-Delivered RNA Pool Contains Small Noncoding RNAs and Interferes with Translation
In plants, the vascular tissue contains the enucleated sieve tubes facilitating long-distance transport of nutrients, hormones, and proteins. In addition, several mRNAs and small interfering RNAs/microRNAs were shown to be delivered via sieve tubes whose content is embodied by the phloem sap (PS). A number of these phloem transcripts are transported from source to sink tissues and function at targeted tissues. To gain additional insights into phloem-delivered RNAs and their potential role in signaling, we isolated and characterized PS RNA molecules distinct from microRNAs/small interfering RNAs with a size ranging from 30 to 90 bases. We detected a high number of full-length and phloem-specific fragments of noncoding RNAs such as tRNAs, ribosomal RNAs, and spliceosomal RNAs in the PS of pumpkin (Cucurbita maxima). In vitro assays show that small quantities of PS RNA molecules efficiently inhibit translation in an unspecific manner. Proof of concept that PS-specific tRNA fragments may interfere with ribosomal activity was obtained with artificially produced tRNA fragments. The results are discussed in terms of a functional role for long distance delivered noncoding PS RNAs.
Journal Article
Cooperative recruitment of RDR6 by SGS3 and SDE5 during small interfering RNA amplification in Arabidopsis
Small interfering RNAs (siRNAs) are often amplified from transcripts cleaved by RNA-induced silencing complexes (RISCs) containing a small RNA (sRNA) and an Argonaute protein. Amplified siRNAs, termed secondary siRNAs, are important for reinforcement of target repression. In plants, target cleavage by RISCs containing 22-nucleotide (nt) sRNA and Argonaute 1 (AGO1) triggers siRNA amplification. In this pathway, the cleavage fragment is converted into double-stranded RNA (dsRNA) by RNA-dependent RNA polymerase 6 (RDR6), and the dsRNA is processed into siRNAs by Dicer-like proteins. Because nonspecific RDR6 recruitment causes nontarget siRNA production, it is critical that RDR6 is specifically recruited to the target RNA that serves as a template for dsRNA formation. Previous studies showed that Suppressor of Gene Silencing 3 (SGS3) binds and stabilizes 22-nt sRNA–containing AGO1 RISCs associated with cleaved target, but how RDR6 is recruited to targets cleaved by 22-nt sRNA–containing AGO1 RISCs remains unknown. Here, using cell-free extracts prepared from suspension-cultured Arabidopsis thaliana cells, we established an in vitro system for secondary siRNA production in which 22-nt siRNA–containing AGO1-RISCs but not 21-nt siRNA–containing AGO1-RISCs induce secondary siRNA production. In this system, addition of recombinant Silencing Defective 5 (SDE5) protein remarkably enhances secondary siRNA production. We show that RDR6 is recruited to a cleavage fragment by 22-nt siRNA–containing AGO1-RISCs in coordination with SGS3 and SDE5. The SGS3–SDE5–RDR6 multicomponent recognition system and the poly(A) tail inhibition may contribute to securing specificity of siRNA amplification.
Journal Article
On the road to reading the RNA-interference code
The finding that sequence-specific gene silencing occurs in response to the presence of double-stranded RNAs has had an enormous impact on biology, uncovering an unsuspected level of regulation of gene expression. This process, known as RNA interference (RNAi) or RNA silencing, involves small non-coding RNAs, which associate with nuclease-containing regulatory complexes and then pair with complementary messenger RNA targets, thereby preventing the expression of these mRNAs. Remarkable progress has been made towards understanding the underlying mechanisms of RNAi, raising the prospect of deciphering the 'RNAi code' that, like transcription factors, allows the fine-tuning and networking of complex suites of gene activity, thereby specifying cellular physiology and development.
Journal Article
Competing endogenous RNAs: a target-centric view of small RNA regulation in bacteria
Many bacterial regulatory small RNAs (sRNAs) have several mRNA targets, which places them at the centre of regulatory networks that help bacteria to adapt to environmental changes. However, different mRNA targets of any given sRNA compete with each other for binding to the sRNA; thus, depending on relative abundances and sRNA affinity, competition for regulatory sRNAs can mediate cross-regulation between bacterial mRNAs. This 'target-centric' perspective of sRNA regulation is reminiscent of the competing endogenous RNA (ceRNA) hypothesis, which posits that competition for a limited pool of microRNAs (miRNAs) in higher eukaryotes mediates cross-regulation of mRNAs. In this Opinion article, we discuss evidence that a similar network of RNA crosstalk operates in bacteria, and that this network also includes crosstalk between sRNAs and competition for RNA-binding proteins.
Similarly to competing endogenous RNAs (ceRNAs) in mammalian cells, competition for regulatory RNAs and proteins can lead to crosstalk between bacterial mRNAs. In this Opinion article, Bossi and Figueroa-Bossi argue that such competition for regulatory targets may have a substantial influence on bacterial gene networks.
Journal Article
CDKF;1 and CDKD Protein Kinases Regulate Phosphorylation of Serine Residues in the C-Terminal Domain of Arabidopsis RNA Polymerase II
Phosphorylation of conserved Y₁S₂P₃T₄S₅P₆S₇ repeats in the C-terminal domain of largest subunit of RNA polymerase II (RNAPII CTD) plays a central role in the regulation of transcription and cotranscriptional RNA processing. Here, we show that Ser phosphorylation of Arabidopsis thaliana RNAPII CTD is governed by CYCLIN-DEPENDENT KINASE F;1 (CDKF;1), a unique plant-specific CTD S₇-kinase. CDKF;1 is required for in vivo activation of functionally redundant CYCLIN-DEPENDENT KINASE Ds (CDKDs), which are major CTD S₅-kinases that also phosphorylate in vitro the S₂ and S₇ CTD residues. Inactivation of CDKF;1 causes extreme dwarfism and sterility. Inhibition of CTD S₇-phosphorylation in germinating cdkf;1 seedlings is accompanied by 3'-polyadenylation defects of pre-microRNAs and transcripts encoding key regulators of small RNA biogenesis pathways. The cdkf;1 mutation also decreases the levels of both precursor and mature small RNAs without causing global downregulation of the protein-coding transcriptome and enhances the removal of introns that carry premicroRNA stem-loops. A triple cdkd knockout mutant is not viable, but a combination of null and weak cdkd;3 alleles in a triple cdkd123* mutant permits semidwarf growth. Germinating cdkd123* seedlings show reduced CTD S₅-phosphorylation, accumulation of uncapped precursor microRNAs, and a parallel decrease in mature microRNA. During later development of cdkd123* seedlings, however, S₇-phosphorylation and unprocessed small RNA levels decline similarly as in the cdkf;1 mutant. Taken together, cotranscriptional processing and stability of a set of small RNAs and transcripts involved in their biogenesis are sensitive to changes in the phosphorylation of RNAPII CTD by CDKF;1 and CDKDs.
Journal Article