Cold Spring Harbor symposia on quantitative biology最新文献

{"title":"To Process or to Decay: A Mechanistic View of the Nuclear RNA Exosome.","authors":"Mahesh Lingaraju,&nbsp;Jan M Schuller,&nbsp;Sebastian Falk,&nbsp;Piotr Gerlach,&nbsp;Fabien Bonneau,&nbsp;Jérôme Basquin,&nbsp;Christian Benda,&nbsp;Elena Conti","doi":"10.1101/sqb.2019.84.040295","DOIUrl":"https://doi.org/10.1101/sqb.2019.84.040295","url":null,"abstract":"<p><p>The RNA exosome was originally discovered in yeast as an RNA-processing complex required for the maturation of 5.8S ribosomal RNA (rRNA), one of the constituents of the large ribosomal subunit. The exosome is now known in eukaryotes as the major 3'-5' RNA degradation machine involved in numerous processing, turnover, and surveillance pathways, both in the nucleus and the cytoplasm. Yet its role in maturing the 5.8S rRNA in the pre-60S ribosomal particle remains probably the most intricate and emblematic among its functions, as it involves all the RNA unwinding, degradation, and trimming activities embedded in this macromolecular complex. Here, we propose a comprehensive mechanistic model, based on current biochemical and structural data, explaining the dual functions of the nuclear exosome-the constructive versus the destructive mode.</p>","PeriodicalId":72635,"journal":{"name":"Cold Spring Harbor symposia on quantitative biology","volume":"84 ","pages":"155-163"},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1101/sqb.2019.84.040295","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38009529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biophysical Properties of HP1-Mediated Heterochromatin.","authors":"Serena Sanulli,&nbsp;John D Gross,&nbsp;Geeta J Narlikar","doi":"10.1101/sqb.2019.84.040360","DOIUrl":"https://doi.org/10.1101/sqb.2019.84.040360","url":null,"abstract":"<p><p>Heterochromatin is a classic context for studying the mechanisms of chromatin organization. At the core of a highly conserved type of heterochromatin is the complex formed between chromatin methylated on histone H3 lysine 9 and HP1 proteins. This type of heterochromatin plays central roles in gene repression, genome stability, and nuclear mechanics. Systematic studies over the last several decades have provided insight into the biophysical mechanisms by which the HP1-chromatin complex is formed. Here, we discuss these studies together with recent findings indicating a role for phase separation in heterochromatin organization and function. We suggest that the different functions of HP1-mediated heterochromatin may rely on the increasing diversity being uncovered in the biophysical properties of HP1-chromatin complexes.</p>","PeriodicalId":72635,"journal":{"name":"Cold Spring Harbor symposia on quantitative biology","volume":"84 ","pages":"217-225"},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1101/sqb.2019.84.040360","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38009532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Conversation with Adrian Krainer.","authors":"","doi":"10.1101/sqb.2019.84.039461","DOIUrl":"https://doi.org/10.1101/sqb.2019.84.039461","url":null,"abstract":"Anke Sparmann: You were awarded the 2019 Breakthrough Prize in Life Sciences together with Dr. Frank Bennett of Ionis Pharmaceuticals for the development of antisense oligonucleotide drugs to target RNA splicing and the incredible success story of SPINRAZA, the first drug approved for spinal muscular atrophy. Can you start by telling us about this devastating disease and the molecular mechanism underlying it that you discovered?","PeriodicalId":72635,"journal":{"name":"Cold Spring Harbor symposia on quantitative biology","volume":"84 ","pages":"276-278"},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1101/sqb.2019.84.039461","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37735331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recognition of Poly(A) RNA through Its Intrinsic Helical Structure.","authors":"Terence T L Tang,&nbsp;Lori A Passmore","doi":"10.1101/sqb.2019.84.039818","DOIUrl":"https://doi.org/10.1101/sqb.2019.84.039818","url":null,"abstract":"<p><p>The polyadenosine (poly(A)) tail, which is found on the 3' end of almost all eukaryotic messenger RNAs (mRNAs), plays an important role in the posttranscriptional regulation of gene expression. Shortening of the poly(A) tail, a process known as deadenylation, is thought to be the first and rate-limiting step of mRNA turnover. Deadenylation is performed by the Pan2-Pan3 and Ccr4-Not complexes that contain highly conserved exonuclease enzymes Pan2, and Ccr4 and Caf1, respectively. These complexes have been extensively studied, but the mechanisms of how the deadenylase enzymes recognize the poly(A) tail were poorly understood until recently. Here, we summarize recent work from our laboratory demonstrating that the highly conserved Pan2 exonuclease recognizes the poly(A) tail, not through adenine-specific functional groups, but through the conformation of poly(A) RNA. Our biochemical, biophysical, and structural investigations suggest that poly(A) forms an intrinsic base-stacked, single-stranded helical conformation that is recognized by Pan2, and that disruption of this structure inhibits both Pan2 and Caf1. This intrinsic structure has been shown to be important in poly(A) recognition in other biological processes, further underlining the importance of the unique conformation of poly(A).</p>","PeriodicalId":72635,"journal":{"name":"Cold Spring Harbor symposia on quantitative biology","volume":"84 ","pages":"21-30"},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1101/sqb.2019.84.039818","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37838503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNP Granule Formation: Lessons from P-Bodies and Stress Granules.","authors":"Giulia Ada Corbet,&nbsp;Roy Parker","doi":"10.1101/sqb.2019.84.040329","DOIUrl":"https://doi.org/10.1101/sqb.2019.84.040329","url":null,"abstract":"<p><p>It is now clear that cells form a wide collection of large RNA-protein assemblies, referred to as RNP granules. RNP granules exist in bacterial cells and can be found in both the cytosol and nucleus of eukaryotic cells. Recent approaches have begun to define the RNA and protein composition of a number of RNP granules. Herein, we review the composition and assembly of RNP granules, as well as how RNPs are targeted to RNP granules using stress granules and P-bodies as model systems. Taken together, these reveal that RNP granules form through the summative effects of a combination of protein-protein, protein-RNA, and RNA-RNA interactions. Similarly, the partitioning of individual RNPs into stress granules is determined by the combinatorial effects of multiple elements. Thus, RNP granules are assemblies generally dominated by combinatorial effects, thereby providing rich opportunities for biological regulation.</p>","PeriodicalId":72635,"journal":{"name":"Cold Spring Harbor symposia on quantitative biology","volume":"84 ","pages":"203-215"},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1101/sqb.2019.84.040329","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37999987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"U1 snRNP Telescripting Roles in Transcription and Its Mechanism.","authors":"Chao Di,&nbsp;Byung Ran So,&nbsp;Zhiqiang Cai,&nbsp;Chie Arai,&nbsp;Jingqi Duan,&nbsp;Gideon Dreyfuss","doi":"10.1101/sqb.2019.84.040451","DOIUrl":"https://doi.org/10.1101/sqb.2019.84.040451","url":null,"abstract":"<p><p>Telescripting is a fundamental cotranscriptional gene regulation process that relies on U1 snRNP (U1) to suppress premature 3'-end cleavage and polyadenylation (PCPA) in RNA polymerase II (Pol II) transcripts, which is necessary for full-length transcription of thousands of protein-coding (pre-mRNAs) and long noncoding (lncRNA) genes. Like U1 role in splicing, telescripting requires U1 snRNA base-pairing with nascent transcripts. Inhibition of U1 base-pairing with U1 snRNA antisense morpholino oligonucleotide (U1 AMO) mimics widespread PCPA from cryptic polyadenylation signals (PASs) in human tissues, including PCPA in introns and last exons' 3'-untranslated regions (3' UTRs). U1 telescripting-PCPA balance changes generate diverse RNAs depending on where in a gene it occurs. Long genes are highly U1-telescripting-dependent because of PASs in introns compared to short genes. Enrichment of cell cycle control, differentiation, and developmental functions in long genes, compared to housekeeping and acute cell stress response genes in short genes, reveals a gene size-function relationship in mammalian genomes. This polarization increased in metazoan evolution by previously unexplained intron expansion, suggesting that U1 telescripting could shift global gene expression priorities. We show that that modulating U1 availability can profoundly alter cell phenotype, such as cancer cell migration and invasion, underscoring the critical role of U1 homeostasis and suggesting it as a potential target for therapies. We describe a complex of U1 with cleavage and polyadenylation factors that silences PASs in introns and 3' UTR, which gives insights into U1 telescripting mechanism and transcription elongation regulation.</p>","PeriodicalId":72635,"journal":{"name":"Cold Spring Harbor symposia on quantitative biology","volume":"84 ","pages":"115-122"},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1101/sqb.2019.84.040451","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38031707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Conversation with Ling-Ling Chen.","authors":"","doi":"10.1101/sqb.2019.84.039032","DOIUrl":"https://doi.org/10.1101/sqb.2019.84.039032","url":null,"abstract":"Dr. Chen: I wouldn’t call it a switch, but really a smooth transition. Ten years ago, one of the most exciting discoveries in molecular biology was pervasive transcription of the genome, leading to the discovery of intergenic-regiontranscribed long noncoding RNAs [lincRNAs]. We know that the transcription and processing of long noncoding RNAs is different from those of mRNAs [messenger RNAs], but at the ends these mature lncRNAs look similar to mRNAs: They have 5′ mG-capping or 3′ poly(A) tails with only a few exceptions, like NEAT1 [Nuclear Enriched Abundant Transcript 1] or MALAT1 [Metastasis-Associated Lung Adenocarcinoma Transcript 1], originally discovered by Dave Spector’s lab right here at Cold Spring Harbor. His lab found that the 3′-end processing of these two basically used an RNase P cleavage related to tRNA [transfer RNA] biogenesis, and those RNAs look so different at the 3′ ends from mRNAs. Luckily, I worked on NEAT1 with Gordon Carmichael at the time. Starting from those Alu elements, I found that mRNAs containing inverted Alu repeats are preferentially retained in the nuclei in bodies called paraspeckles. I found that NEAT1 is a major organizer of paraspeckles. So, triggered by the very interesting, different appearance of NEAT1, I asked the question: Do all RNAs look the same as mRNAs? From there, I began to explore the nonpoly(A) transcriptome, which had been ignored by so many people as just junk. We discovered different classes of previously unknown species. These RNAs do not have their own promoters, but rather are processed from the primary Pol II [RNA Polymerase II] transcripts and then stabilized by distinct mechanisms like forming RNA circles, or by the protection of snoRNP [small nucleolar RNA–protein] complexes at one or both ends. More importantly, now we’ve figured out that some of them can impact important functions of gene regulation in cells that also relate to human diseases including Prader–Willi syndrome and autoimmune diseases like lupus. We’re happy to see that these previously thought-of-as-junk things can do something in cells.","PeriodicalId":72635,"journal":{"name":"Cold Spring Harbor symposia on quantitative biology","volume":"84 ","pages":"262-263"},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1101/sqb.2019.84.039032","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37479825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic Dissection of RNA-Binding Proteins in Regulated Gene Expression at Chromatin Levels.","authors":"Jia-Yu Chen, Do-Hwan Lim, Xiang-Dong Fu","doi":"10.1101/sqb.2019.84.039222","DOIUrl":"10.1101/sqb.2019.84.039222","url":null,"abstract":"<p><p>Eukaryotic genomes are known to prevalently transcribe diverse classes of RNAs, virtually all of which, including nascent RNAs from protein-coding genes, are now recognized to have regulatory functions in gene expression, suggesting that RNAs are both the products and the regulators of gene expression. Their functions must enlist specific RNA-binding proteins (RBPs) to execute their regulatory activities, and recent evidence suggests that nearly all biochemically defined chromatin regions in the human genome, whether defined for gene activation or silencing, have the involvement of specific RBPs. Interestingly, the boundary between RNA- and DNA-binding proteins is also melting, as many DNA-binding proteins traditionally studied in the context of transcription are able to bind RNAs, some of which may simultaneously bind both DNA and RNA to facilitate network interactions in three-dimensional (3D) genome. In this review, we focus on RBPs that function at chromatin levels, with particular emphasis on their mechanisms of action in regulated gene expression, which is intended to facilitate future functional and mechanistic dissection of chromatin-associated RBPs.</p>","PeriodicalId":72635,"journal":{"name":"Cold Spring Harbor symposia on quantitative biology","volume":"84 ","pages":"55-66"},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332398/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37511828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Summary: Order and Disorder in Brains and Behavior.","authors":"Adam Kepecs","doi":"10.1101/sqb.2018.83.038885","DOIUrl":"https://doi.org/10.1101/sqb.2018.83.038885","url":null,"abstract":"The 83rd Cold Spring Harbor Symposium on Quantitative Biology on Brains and Behavior: Order and Disorder in the Nervous System explored the tremendous recent progress in neuroscience and how these advances may be used to improve brain health and address psychiatric and neurological disorders. The Symposium explored a vast array of topics from cell types to cognition. My summary focuses on a few emerging themes. Innovative techniques were ever-present, opening up new experimental possibilities. The commoditization of many state-of-the-art technologies is pushing neuroscience beyond its artisanal ways. Another important theme was \"circuits in the middle\": Numerous presentations dissected links to cell type-specific circuits that connect different levels of analysis from molecules to behavior. These new technologies have enabled curiosity-driven investigations in animals to connect more directly with preclinical and clinical studies of human brain disorders. Numerous emerging approaches were presented in human neuroscience, bolstering the hope that circuit-specific manipulations will soon provide improved treatments for brain disorders.","PeriodicalId":72635,"journal":{"name":"Cold Spring Harbor symposia on quantitative biology","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83337497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The THO Complex as a Paradigm for the Prevention of Cotranscriptional R-Loops.","authors":"Rosa Luna,&nbsp;Ana G Rondón,&nbsp;Carmen Pérez-Calero,&nbsp;Irene Salas-Armenteros,&nbsp;Andrés Aguilera","doi":"10.1101/sqb.2019.84.039594","DOIUrl":"https://doi.org/10.1101/sqb.2019.84.039594","url":null,"abstract":"<p><p>Different proteins associate with the nascent RNA and the RNA polymerase (RNAP) to catalyze the transcription cycle and RNA export. If these processes are not properly controlled, the nascent RNA can thread back and hybridize to the DNA template forming R-loops capable of stalling replication, leading to DNA breaks. Given the transcriptional promiscuity of the genome, which leads to large amounts of RNAs from mRNAs to different types of ncRNAs, these can become a major threat to genome integrity if they form R-loops. Consequently, cells have evolved nuclear factors to prevent this phenomenon that includes THO, a conserved eukaryotic complex acting in transcription elongation and RNA processing and export that upon inactivation causes genome instability linked to R-loop accumulation. We revise and discuss here the biological relevance of THO and a number of RNA helicases, including the THO partner UAP56/DDX39B, as a paradigm of the cellular mechanisms of cotranscriptional R-loop prevention.</p>","PeriodicalId":72635,"journal":{"name":"Cold Spring Harbor symposia on quantitative biology","volume":"84 ","pages":"105-114"},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1101/sqb.2019.84.039594","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38009534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}