Sen1 has unique structural features grafted on the architecture of the Upf1‐like helicase family

The superfamily 1B (SF1B) helicase Sen1 is an essential protein that plays a key role in the termination of non‐coding transcription in yeast. Here, we identified the ~90 kDa helicase core of Saccharomyces cerevisiae Sen1 as sufficient for transcription termination in vitro and determined the corresponding structure at 1.8 Å resolution. In addition to the catalytic and auxiliary subdomains characteristic of the SF1B family, Sen1 has a distinct and evolutionarily conserved structural feature that “braces” the helicase core. Comparative structural analyses indicate that the “brace” is essential in shaping a favorable conformation for RNA binding and unwinding. We also show that subdomain 1C (the “prong”) is an essential element for 5′‐3′ unwinding and for Sen1‐mediated transcription termination in vitro. Finally, yeast Sen1 mutant proteins mimicking the disease forms of the human orthologue, senataxin, show lower capacity of RNA unwinding and impairment of transcription termination in vitro. The combined biochemical and structural data thus provide a molecular model for the specificity of Sen1 in transcription termination and more generally for the unwinding mechanism of 5′‐3′ helicases.

• Publication year

  2017

• Venue

  EMBO Journal

• Publication date

  2017-04-13

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.15252/embj.201696174PMID 28408439PMCID 5452015
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Sen1 has unique structural features grafted on the architecture of the Upf1‐like helicase family

  2017cited by this paper
• Saccharomyces cerevisiae Sen1 Helicase Domain Exhibits 5′- to 3′-Helicase Activity with a Preference for Translocation on DNA Rather than RNA*♦

  2015cited by this paper
• Characterization of the mechanisms of transcription termination by the helicase Sen1.

  2015influential reference
• Human Upf1 is a highly processive RNA helicase and translocase with RNP remodelling activities

  2015cited by this paper
• Termination of Transcription of Short Noncoding RNAs by RNA Polymerase II.

  2015cited by this paper
• The conformational plasticity of eukaryotic RNA‐dependent ATPases

  2015cited by this paper
• Unwinding the role of senataxin in neurodegeneration.

  2015cited by this paper
• SMN and symmetric arginine dimethylation of RNA polymerase II C-terminal domain control termination

  2015cited by this paper
• The Phyre2 web portal for protein modeling, prediction and analysis

  2015cited by this paper
• PRIGo: a new multi-axis goniometer for macromolecular crystallography

  2015influential reference
• Transcription termination and the control of the transcriptome: why, where and how to stop

  2015influential reference
• Supplemental Information Molecular Basis for Coordinating Transcription Termination with Noncoding RNA Degradation

  2014cited by this paper
• Fast native-SAD phasing for routine macromolecular structure determination

  2014influential reference
• Saccharomyces cerevisiae Sen1 as a Model for the Study of Mutations in Human Senataxin That Elicit Cerebellar Ataxia

  2014influential reference
• Structural and functional insights into the human Upf 1 helicase core

  2013cited by this paper
• Transcriptome surveillance by selective termination of noncoding RNA synthesis.

  2013cited by this paper
• Disengaging polymerase: Terminating RNA polymerase II transcription in budding yeast☆

  2013cited by this paper
• Dealing with pervasive transcription.

  2013cited by this paper
• A bacterial-like mechanism for transcription termination by the Sen1p helicase in budding yeast

  2013influential reference
• The Ighmbp2 helicase structure reveals the molecular basis for disease-causing mutations in DMSA1

  2012cited by this paper
• Unwinding initiation by the viral RNA helicase NPH-II.

  2012cited by this paper
• Linking Crystallographic Model and Data Quality

  2012cited by this paper
• In vivo SELEX reveals novel sequence and structural determinants of Nrd1‐Nab3‐Sen1‐dependent transcription termination

  2012cited by this paper
• The nuclear RNA polymerase II surveillance system targets polymerase III transcripts

  2011cited by this paper
• Yeast Sen1 Helicase Protects the Genome from Transcription-Associated Instability

  2011cited by this paper
• Production and single-step purification of EGFP and a biotinylated version of the Human Rhinovirus 14 3C protease.

  2011cited by this paper
• Human Senataxin Resolves RNA/DNA Hybrids Formed at Transcriptional Pause Sites to Promote Xrn2-Dependent Termination

  2011cited by this paper
• Molecular mechanisms for the RNA-dependent ATPase activity of Upf1 and its regulation by Upf2.

  2011influential reference
• Experimental phasing with SHELXC/D/E: combining chain tracing with density modification

  2010cited by this paper
• Integration, scaling, space-group assignment and post-refinement

  2010cited by this paper
• Structural analysis reveals the characteristic features of Mtr4, a DExH helicase involved in nuclear RNA processing and surveillance

  2010cited by this paper
• The crystal structure of Mtr4 reveals a novel arch domain required for rRNA processing

  2010cited by this paper
• Simplified, Enhanced Protein Purification Using an Inducible, Autoprocessing Enzyme Tag

  2009cited by this paper
• Functional role for senataxin, defective in ataxia oculomotor apraxia type 2, in transcriptional regulation.

  2009cited by this paper
• An auxin-based degron system for the rapid depletion of proteins in nonplant cells

  2009cited by this paper
• Unusual bipartite mode of interaction between the nonsense‐mediated decay factors, UPF1 and UPF2

  2009cited by this paper
• Translocation and unwinding mechanisms of RNA and DNA helicases.

  2008cited by this paper
• NMD factors UPF2 and UPF3 bridge UPF1 to the exon junction complex and stimulate its RNA helicase activity

  2008cited by this paper
• Interaction of yeast RNA-binding proteins Nrd1 and Nab3 with RNA polymerase II terminator elements.

  2007cited by this paper
• Structural basis for DNA duplex separation by a superfamily-2 helicase

  2007cited by this paper
• Structural and functional insights into the human Upf1 helicase core

  2007cited by this paper
• Bent out of shape: RNA unwinding by the DEAD-box helicase Vasa.

  2006cited by this paper
• Genome-wide distribution of yeast RNA polymerase II and its control by Sen1 helicase.

  2006cited by this paper
• The Buccaneer software for automated model building. 1. Tracing protein chains.

  2006cited by this paper
• Structural basis for RNA unwinding by the DEAD-box protein Drosophila Vasa.

  2006cited by this paper
• RNA degradation by the exosome is promoted by a nuclear polyadenylation complex.

  2005cited by this paper
• A New Yeast Poly(A) Polymerase Complex Involved in RNA Quality Control

  2005cited by this paper
• Cryptic pol II transcripts are degraded by a nuclear quality control pathway involving a new poly(A) polymerase.

  2005cited by this paper
• The HHpred interactive server for protein homology detection and structure prediction

  2005cited by this paper
• Multiple protein/protein and protein/RNA interactions suggest roles for yeast DNA/RNA helicase Sen1p in transcription, transcription-coupled DNA repair and RNA processing.

  2004cited by this paper
• HKL2MAP: a graphical user interface for macromolecular phasing with SHELX programs

  2004cited by this paper
• The newly discovered Q motif of DEAD‐box RNA helicases regulates RNA‐binding and helicase activity

  2004cited by this paper
• Coot: model-building tools for molecular graphics.

  2004cited by this paper
• Assays and affinity purification of biotinylated and nonbiotinylated forms of double-tagged core RNA polymerase II from Saccharomyces cerevisiae.

  2003cited by this paper
• Characterization of the biochemical properties of the human Upf1 gene product that is involved in nonsense-mediated mRNA decay.

  2000cited by this paper
• The sen1(+) gene of Schizosaccharomyces pombe, a homologue of budding yeast SEN1, encodes an RNA and DNA helicase.

  1999cited by this paper
• Functions of the exosome in rRNA, snoRNA and snRNA synthesis

  1999cited by this paper
• Γ Decay

  1999cited by this paper
• Crystal structures of complexes of PcrA DNA helicase with a DNA substrate indicate an inchworm mechanism.

  1999cited by this paper
• Repression of gene expression by an exogenous sequence element acting in concert with a heterogeneous nuclear ribonucleoprotein-like protein, Nrd1, and the putative helicase Sen1

  1996cited by this paper
• Improvements in the numerical analysis of thermodynamic data from biomolecular complexes.

  1993cited by this paper
• SEN1, a positive effector of tRNA-splicing endonuclease in Saccharomyces cerevisiae

  1992cited by this paper
• Electronic Reprint Biological Crystallography Phenix : a Comprehensive Python-based System for Macromolecular Structure Solution

  year unknowncited by this paper

• Senataxin and DNA-PKcs redundantly promote non-homologous end joining repair of DNA double strand breaks during V(D)J recombination

  2025cites this paper
• Allele-specific silencing of a dominant SETX mutation in familial amyotrophic lateral sclerosis type 4

  2025cites this paper
• A role for human senataxin in contending with pausing and backtracking during transcript elongation.

  2025cites this paper
• Functional investigation of the RNA helicase MOV10 with respect to its interplay with factors involved in nonsense-mediated mRNA decay

  2025cites this paper
• Sen1: the varied virtues of a multifaceted helicase.

  2024cites this paper
• Senataxin and DNA-PKcs Redundantly Promote Non-Homologous End Joining Repair of DNA Double Strand Breaks During V(D)J Recombination

  2024cites this paper
• A Compendium of G-Flipon Biological Functions That Have Experimental Validation

  2024cites this paper
• Role of senataxin in R-loop-mediated neurodegeneration

  2024cites this paper
• Single-molecule reconstruction of eukaryotic factor-dependent transcription termination

  2024cites this paper
• Senataxin deficiency disrupts proteostasis through nucleolar ncRNA-driven protein aggregation

  2024cites this paper
• Single-molecule characterization of Sen1 translocation properties provides insights into eukaryotic factor-dependent transcription termination

  2024cites this paper
• The contribution and therapeutic implications of IGHMBP2 mutations on IGHMBP2 biochemical activity and ABT1 association.

  2024cites this paper
• Mechanism of polyadenylation-independent RNA polymerase II termination

  2024cites this paper
• Allele-specific silencing of a dominant SETX mutation in familial amyotrophic lateral sclerosis type 4

  2024cites this paper
• Expression, purification, and biochemical analysis of the RNA-DNA hybrid helicase Sen1/SETX from Chaetomium thermophilum.

  2024cites this paper
• Unveiling the mechanism of Sen1 translocation

  2023cites this paper
• Role of Senataxin in Amyotrophic Lateral Sclerosis

  2023cites this paper
• Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar Atrophy

  2023cites this paper
• Sen1 architecture: RNA-DNA hybrid resolution, autoregulation, and insights into SETX inactivation in AOA2.

  2023cites this paper
• Senataxin: A key actor in RNA metabolism, genome integrity and neurodegeneration.

  2023cites this paper
• The Nrd1–Nab3–Sen1 transcription termination complex from a structural perspective

  2023cites this paper
• Clinical and Mechanistic Implications of R-Loops in Human Leukemias

  2023cites this paper
• Pervasive transcription: a controlled risk

  2022cites this paper
• Structural insights into nuclear transcription by eukaryotic DNA-dependent RNA polymerases

  2022cites this paper
• R-Loop Formation in Meiosis: Roles in Meiotic Transcription-Associated DNA Damage

  2022cites this paper
• Human senataxin is a bona fide R-loop resolving enzyme and transcription termination factor

  2022cites this paper
• Modulated termination of non-coding transcription partakes in the regulation of gene expression

  2021influential citation
• An integrated model for termination of RNA polymerase III transcription

  2021influential citation
• Untangling the crosstalk between BRCA1 and R-loops during DNA repair

  2021cites this paper
• Gain-of-function mutagenesis through activation tagging identifies XPB2 and SEN1 helicase genes as potential targets for drought stress tolerance in rice

  2021cites this paper
• Termination of non‐coding transcription in yeast relies on both an RNA Pol II CTD interaction domain and a CTD‐mimicking region in Sen1

  2020cites this paper
• Sen1 Is Recruited to Replication Forks via Ctf4 and Mrc1 and Promotes Genome Stability

  2020cites this paper
• Modelling the active SARS-CoV-2 helicase complex as a basis for structure-based inhibitor design

  2020cites this paper
• Gain of function mutagenesis through activation tagging identifies XPB2 and SEN1 helicase genes as potential targets for drought stress tolerance in rice

  2020influential citation
• Senataxin: A Putative RNA: DNA Helicase Mutated in ALS4—Emerging Mechanisms of Genome Stability in Motor Neurons

  2020cites this paper
• Making routine native SAD a reality: lessons from beamline X06DA at the Swiss Light Source

  2019cites this paper
• Genome-Wide Discovery of DEAD-Box RNA Helicase Targets Reveals RNA Structural Remodeling in Transcription Termination

  2019cites this paper
• Writing a wrong: Coupled RNA polymerase II transcription and RNA quality control

  2019cites this paper
• Biallelic variants in DNA2 cause microcephalic primordial dwarfism

  2019cites this paper
• HELZ directly interacts with CCR4–NOT and causes decay of bound mRNAs

  2019cites this paper
• Long-wavelength native-SAD phasing: opportunities and challenges

  2019cites this paper
• Single-molecule characterization of extrinsic transcription termination by Sen1 helicase

  2019cites this paper
• Structural and biochemical studies of the S. cerevisiae DNA/RNA helicase Sen1

  2018cites this paper
• Senataxin resolves RNA:DNA hybrids forming at DNA double-strand breaks to prevent translocations

  2018cites this paper
• Mechanism for the Regulated Control of Bacterial Transcription Termination by a Universal Adaptor Protein.

  2018cites this paper
• Analysis of mRNA 3' tagging pathway components

  2018cites this paper
• Termination of non-coding transcription in yeast relies on both a CTD-interaction domain and a CTD-mimic in Sen1

  2018cites this paper
• Étude biochimique et biophysique de l’ARN hélicase UPF1 : un moteur moléculaire hautement régulé

  2018cites this paper
• UPF1-like helicase grip on nucleic acids dictates processivity

  2018cites this paper
• The universally conserved GTPase HflX is an RNA helicase that restores heat-damaged Escherichia coli ribosomes

  2018cites this paper
• Helicases as transcription termination factors: Different solutions for a common problem

  2018cites this paper
• RNA Polymerase II Transcription Attenuation at the Yeast DNA Repair Gene, DEF1, Involves Sen1-Dependent and Polyadenylation Site-Dependent Termination

  2018cites this paper
• Transcriptomes of six mutants in the Sen1 pathway reveal combinatorial control of transcription termination across the Saccharomyces cerevisiae genome

  2017cites this paper
• Sen1 has unique structural features grafted on the architecture of the Upf1‐like helicase family

  2017cites this paper