Abstract：
:The Rbfox family of splicing factors regulate alternative splicing during animal development and in disease, impacting thousands of exons in the maturing brain, heart and muscle. Rbfox proteins have long been known to bind to the RNA sequence GCAUG with high affinity and specificity, but just half of Rbfox binding sites contain a GCAUG motif in vivo. We incubated recombinant RBFOX2 with over 60,000 mouse and human transcriptomic sequences to reveal substantial binding to several moderate-affinity, non-GCAYG sites at a physiologically relevant range of RBFOX2 concentrations. We find that these 'secondary motifs' bind Rbfox robustly in cells and that several together can exert regulation comparable to GCAUG in a trichromatic splicing reporter assay. Furthermore, secondary motifs regulate RNA splicing in neuronal development and in neuronal subtypes where cellular Rbfox concentrations are highest, enabling a second wave of splicing changes as Rbfox levels increase.
journal_name
Nat Struct Mol Bioljournal_title
Nature structural & molecular biologyauthors
Begg BE,Jens M,Wang PY,Minor CM,Burge CBdoi
10.1038/s41594-020-0475-8subject
Has Abstractpub_date
2020-10-01 00:00:00pages
901-912issue
10eissn
1545-9993issn
1545-9985pii
10.1038/s41594-020-0475-8journal_volume
27pub_type
杂志文章abstract：:Bacterial tRNA adenosine deaminases (TadAs) catalyze the hydrolytic deamination of adenosine to inosine at the wobble position of tRNA(Arg2), a process that enables this single tRNA to recognize three different arginine codons in mRNA. In addition, inosine is also introduced at the wobble position of multiple eukaryot...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/nsmb1047
更新日期：2006-02-01 00:00:00
abstract：:The core of the neurotransmitter release machinery is formed by SNARE complexes, which bring the vesicle and plasma membranes together and are key for fusion, and by Munc18-1, which controls SNARE-complex formation and may also have a direct role in fusion. In addition, SNARE complex assembly is likely orchestrated by...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章,评审
doi：10.1038/nsmb.1450
更新日期：2008-07-01 00:00:00
abstract：:Ribosomes catalyze the formation of peptide bonds between aminoacyl esters of transfer RNAs within a catalytic center composed of ribosomal RNA only. Here we show that the reaction of P-site formylmethionine (fMet)-tRNA(fMet) with a modified A-site tRNA substrate, Phelac-tRNA(Phe), in which the nucleophilic amino grou...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/nsmb1091
更新日期：2006-05-01 00:00:00
abstract：:In budding yeast, DNA damage in G1 activates a Rad9-dependent checkpoint that targets the cyclin-dependent kinase (CDK) Cdc28 to delay G1 exit. After a transient arrest, cells may enter S phase before completing DNA repair. We used genetic analysis to identify the stress-responsive CDK Pho85, the cyclin Pho80 and the ...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/nsmb1139
更新日期：2006-10-01 00:00:00
abstract：:The RNA-induced transcriptional silencing (RITS) complex, containing Ago1, Chp1, Tas3 and centromeric small interfering RNAs (siRNAs), is required for heterochromatic gene silencing at centromeres. Here, we identify a second fission yeast Argonaute complex (Argonaute siRNA chaperone, ARC), which contains, in addition ...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/nsmb1211
更新日期：2007-03-01 00:00:00
abstract：:Agents that activate expression of specific genes to probe cellular pathways or alleviate disease would go beyond existing approaches for controlling gene expression. Duplex RNAs complementary to promoter regions can repress or activate gene expression. The mechanism of these promoter-directed antigene RNAs (agRNAs) h...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/nsmb.1444
更新日期：2008-08-01 00:00:00
abstract：: ...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/s41594-018-0167-9
更新日期：2018-12-01 00:00:00
abstract：:In bacteria, incorporation of selenocysteine, the 21(st) amino acid, into proteins requires elongation factor SelB, which has the unusual property of binding to both transfer RNA (tRNA) and mRNA. SelB binds to an mRNA hairpin formed by the selenocysteine insertion sequence (SECIS) with extremely high specificity, the ...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/nsmb890
更新日期：2005-02-01 00:00:00
abstract：:Protein quality control depends on the tight regulation of interactions between molecular chaperones and polypeptide substrates. Substrate release from the chaperone Hsp70 is triggered by nucleotide-exchange factors (NEFs) that control folding and degradation fates via poorly understood mechanisms. We found that the a...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/s41594-017-0008-2
更新日期：2018-01-01 00:00:00
abstract：:Coupling between transcription and RNA processing is a key gene regulatory mechanism. Here we use chromatin immunoprecipitation to detect transcription-dependent accumulation of the precursor mRNA (pre-mRNA) splicing factors hnRNP A1, U2AF65 and U1 and U5 snRNPs on the intron-containing human FOS gene. These factors w...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/nsmb1135
更新日期：2006-09-01 00:00:00
abstract：:In eukaryotic cells, many introns are constitutively, rather than alternatively, spliced and therefore do not contribute to isoform diversification. It has remained unclear what functional roles such constitutive splicing provides. To explore this issue, we asked how splicing affects the efficiency with which individu...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/s41594-019-0226-x
更新日期：2019-06-01 00:00:00
abstract：:The spliceosome is thought to undergo a conformational change between the two catalytic steps of precursor messenger RNA splicing, although the specific events in this transition are poorly understood. We previously proposed a two-state model of splicing in which the conformations required for the first and second ste...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/nsmb1240
更新日期：2007-06-01 00:00:00
abstract：:Chromatin is a dynamic structure that must respond to myriad stimuli to regulate access to DNA, and chemical modification of histones is a major means by which the cell modulates nucleosome mobility and turnover. Histone modifications are linked to essentially every cellular process requiring DNA access, including tra...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章,评审
doi：10.1038/nsmb.2470
更新日期：2013-03-01 00:00:00
abstract：:Simultaneous profiling of transcriptome and chromatin accessibility within single cells is a powerful approach to dissect gene regulatory programs in complex tissues. However, current tools are limited by modest throughput. We now describe an ultra high-throughput method, Paired-seq, for parallel analysis of transcrip...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/s41594-019-0323-x
更新日期：2019-11-01 00:00:00
abstract：:Many viruses bypass canonical cap-dependent translation in host cells by using internal ribosomal entry sites (IRESs) in their transcripts; IRESs hijack initiation factors for the assembly of initiation complexes. However, it is currently unknown how IRES RNAs recognize initiation factors that have no endogenous RNA b...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/nsmb.3280
更新日期：2016-09-01 00:00:00
abstract：:The nonsense-mediated mRNA decay (NMD) pathway degrades mRNAs undergoing premature termination of translation. It has been argued that in human cells, NMD is restricted to a pioneer round of translation initiated on mRNAs associated with the cap-binding complex (CBC) and that the exchange of the CBC for the eIF4F tran...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/nsmb.2575
更新日期：2013-06-01 00:00:00
abstract：:The N-end rule pathway is a regulated proteolytic system that targets proteins containing destabilizing N-terminal residues (N-degrons) for ubiquitination and proteasomal degradation in eukaryotes. The N-degrons of type 1 substrates contain an N-terminal basic residue that is recognized by the UBR box domain of the E3...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/nsmb.1907
更新日期：2010-10-01 00:00:00
abstract：:Bacterial transcription is controlled by sigma factors, the RNA polymerase subunits that act as initiation factors. Although a single housekeeping sigma factor enables transcription from thousands of promoters, environmentally induced sigma factors redirect gene expression toward small regulons to carry out focused re...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/nsmb.2777
更新日期：2014-03-01 00:00:00
abstract：:The ubiquitination cascade has a key role in the assembly of repair and signaling proteins at sites of double-strand DNA breaks. The E3 ubiquitin ligase RING finger protein 8 (RNF8) triggers the initial ubiquitination at double-strand DNA breaks, whereas sustained ubiquitination requires the downstream E3 ligase RING ...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/nsmb.2211
更新日期：2012-01-22 00:00:00
abstract：:Nuclear volume and the number of nuclear pore complexes (NPCs) on the nucleus almost double during interphase in dividing cells. How these events are coordinated with the cell cycle is poorly understood, particularly in mammalian cells. We report here, based on newly developed techniques for visualizing NPC formation,...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/nsmb.1878
更新日期：2010-09-01 00:00:00
abstract：:Gene expression is inherently stochastic; precise gene regulation by transcription factors is important for cell-fate determination. Many transcription factors regulate their own expression, suggesting that autoregulation counters intrinsic stochasticity in gene expression. Using a new strategy, cotranslational activa...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/nsmb.2336
更新日期：2012-08-01 00:00:00
abstract：:Synthesis of ATP from ADP and phosphate, catalyzed by F(0)F(1)-ATP synthases, is the most abundant physiological reaction in almost any cell. F(0)F(1)-ATP synthases are membrane-bound enzymes that use the energy derived from an electrochemical proton gradient for ATP formation. We incorporated double-labeled F(0)F(1)-...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/nsmb718
更新日期：2004-02-01 00:00:00
abstract：:Ubiquitination is a post-translational modification (PTM) that is essential for balancing numerous physiological processes. To enable delineation of protein ubiquitination at a site-specific level, we generated an antibody, denoted UbiSite, recognizing the C-terminal 13 amino acids of ubiquitin, which remain attached ...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/s41594-018-0084-y
更新日期：2018-07-01 00:00:00
abstract：:The ISWI family of ATP-dependent chromatin remodelers represses transcription by changing nucleosome positions. ISWI regulates nucleosome positioning by requiring a minimal length of extranucleosomal DNA for moving nucleosomes. ISW2 from Saccharomyces cerevisiae, a member of the ISWI family, has a conserved domain cal...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/nsmb.2486
更新日期：2013-02-01 00:00:00
abstract：:Phosphorylation of the spliceosome is essential for RNA splicing, yet how and to what extent kinase signaling affects splicing have not been defined on a genome-wide basis. Using a chemical genetic approach, we show in Schizosaccharomyces pombe that the SR protein kinase Dsk1 is required for efficient splicing of intr...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/nsmb.3057
更新日期：2015-08-01 00:00:00
abstract：:The monoclonal antibody 13H11 shares part of its epitope in the HIV-1 gp41 membrane-proximal external region (MPER) with the rare, broadly neutralizing human antibody 2F5. Although 13H11 partially cross-blocked 2F5 binding, 13H11 is non-neutralizing and does not block 2F5 neutralization. We show that unlike 2F5, 13H11...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/nsmb.1944
更新日期：2010-12-01 00:00:00
abstract：:Primary microRNA cleavage by the Drosha-Dgcr8 'Microprocessor' complex is critical for microRNA biogenesis. Yet, the Microprocessor may also cleave other nuclear RNAs in a nonspecific manner. We studied Microprocessor function using mathematical modeling and experiments in mouse and human tissues. We found that the au...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/nsmb.2293
更新日期：2012-05-13 00:00:00
abstract：:During homologous recombination, Rad51 forms a nucleoprotein filament with single-stranded DNA (ssDNA) that undergoes strand exchange with homologous double-stranded DNA (dsDNA). Here, we use real-time analysis to show that strand exchange by fission yeast Rad51 proceeds via two distinct three-strand intermediates, C1...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/s41594-017-0002-8
更新日期：2018-01-01 00:00:00
abstract：:The tumor suppressor p53 has been proposed to bind target promoters upon genotoxic stress. However, recent evidence shows that p53 occupies some target promoters without such stress, suggesting that a negative regulator might render p53 transcriptionally inactive on these promoters. Here we show that calcineurin bindi...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/nsmb.1657
更新日期：2009-09-01 00:00:00
abstract：:The iota toxin produced by Clostridium perfringens type E is a binary toxin comprising two independent polypeptides: Ia, an ADP-ribosyltransferase, and Ib, which is involved in cell binding and translocation of Ia across the cell membrane. Here we report cryo-EM structures of the translocation channel Ib-pore and its ...
journal_title：Nature structural & molecular biology
pub_type： 杂志文章
doi：10.1038/s41594-020-0388-6
更新日期：2020-03-01 00:00:00
