Affinage

SETX

Helicase senataxin · UniProt Q7Z333

Length
2677 aa
Mass
302.9 kDa
Annotated
2026-04-28
100 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SETX (senataxin) and its yeast orthologs Sen1/SpSen1 encode a 5′-to-3′ SF1B RNA/DNA helicase that serves as a central coordinator of transcription termination, R-loop resolution, and genome stability at sites of transcription–replication conflict. The helicase domain translocates along nascent RNA to dissociate RNA Pol II elongation complexes via an inchworm-like mechanism involving a single-nucleotide power stroke, with an autoinhibitory N-terminal domain that occludes the RNA-binding cleft; in yeast, Sen1 forms the NNS complex with Nrd1 and Nab3 through three Nrd1-interaction motifs to terminate non-coding transcription, and is recruited to replisomes via Ctf4 and Mrc1 to resolve transcription–replication conflicts (PMID:37832548, PMID:31104813, PMID:32075754, PMID:28180347). In human cells, SETX resolves R-loops cooperatively with BRCA1-BARD1 (stimulated by Ser642 phosphorylation), interacts with the exosome subunit Rrp45 in a SUMO-dependent manner, and limits R-loop–driven genome instability at double-strand breaks by preventing aberrant end resection and break-induced replication; loss of SETX causes chromosome fragility, under-replication, and synthetic lethality with FANCD2, RAD52, and PIF1 (PMID:41917467, PMID:24105744, PMID:41037402, PMID:36543851). Recessive loss-of-function mutations cause ataxia with oculomotor apraxia type 2 (AOA2) by disrupting RNA binding and sumoylation-dependent exosome interaction, while dominant ALS4 mutations (e.g., R2136H, L389S) produce gain-of-function neurodegeneration with TDP-43 mislocalization and impaired nucleocytoplasmic transport (PMID:15106121, PMID:29725819, PMID:24105744).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1992 High

    Identification of yeast SEN1 as a nuclear gene required for pre-tRNA splicing established it as an RNA processing factor with NTP-binding motifs homologous to the UPF1 helicase superfamily.

    Evidence Genetic complementation, in vitro endonuclease assays, domain deletion analysis in S. cerevisiae

    PMID:1569945

    Open questions at the time
    • Enzymatic mechanism (helicase vs. endonuclease cofactor) was unresolved
    • Substrate range beyond tRNA was unknown
  2. 1997 High

    Demonstrating that Sen1 is required for processing of tRNAs, rRNAs, and snoRNAs—and physically associates with snoRNAs—expanded its role from a tRNA-specific factor to a general nuclear RNA processing enzyme.

    Evidence Temperature-shift experiments, RNA abundance analysis, co-immunoprecipitation of snoRNAs with Sen1 in yeast

    PMID:9365256

    Open questions at the time
    • Whether Sen1 directly processes these RNAs or acts indirectly was unclear
    • Biochemical activity had not been measured
  3. 1999 High

    Biochemical reconstitution of the S. pombe ortholog as a 5′-to-3′ RNA/DNA helicase and ATPase established the core enzymatic activity, resolving whether Sen1 family proteins are bona fide helicases.

    Evidence Purified SpSen1p; in vitro ATPase, unwinding of RNA:DNA and DNA:RNA duplexes, directionality assays

    PMID:10545196

    Open questions at the time
    • Whether this activity extends to the budding yeast and human orthologs was untested
    • In vivo substrates remained undefined
  4. 2004 High

    Positional cloning of SETX as the gene mutated in ALS4 linked this helicase family to human neurodegeneration and identified specific missense mutations (T3I, L389S, R2136H) in the human ortholog.

    Evidence Linkage analysis and mutation screening in ALS4 families

    PMID:15106121

    Open questions at the time
    • Whether ALS4 mutations cause loss or gain of function was unknown
    • The cellular pathomechanism was undefined
  5. 2006 High

    Genome-wide ChIP mapping revealed that Sen1 controls RNA Pol II distribution across the entire yeast genome, establishing it as a transcription regulator rather than solely an RNA processing factor.

    Evidence Genome-wide Pol II ChIP in wild-type vs. sen1 mutant yeast

    PMID:17157256

    Open questions at the time
    • Whether Sen1 acts directly on Pol II or indirectly through RNA processing was unresolved
    • The termination mechanism was not biochemically defined
  6. 2008 High

    Structural and biochemical characterization of the Nrd1 CID–Pol II CTD interaction explained how Sen1 is recruited specifically to promoter-proximal Pol II (Ser5-P CTD) as part of the NNS termination complex.

    Evidence Crystal structure of Nrd1 CID; CTD phosphopeptide binding assays

    PMID:18660819

    Open questions at the time
    • Direct Sen1–Nrd1 binding interface was not yet structurally resolved
    • How Sen1 itself contacts Pol II was unknown
  7. 2011 High

    Three concurrent advances defined Sen1's roles in R-loop suppression, regulated termination, and chromatin-dependent termination: Sen1 restricts R-loop accumulation to prevent transcription-associated recombination; Mpk1 MAPK prevents premature Sen1-dependent termination of stress genes by blocking NNS recruitment via Paf1; and H3K4me3/Set1 facilitates NNS-dependent termination through Nrd1 recruitment.

    Evidence Genetic epistasis with DNA repair mutants and R-loop assays (R-loops); Paf1–Mpk1 interaction mutants and transcription assays (stress regulation); set1Δ/nrd1 epistasis and Nrd1 ChIP (chromatin)

    PMID:21211720 PMID:21376235 PMID:21709022

    Open questions at the time
    • Whether R-loop resolution and termination are mechanistically coupled or independent functions was unclear
    • Chromatin regulation of NNS was studied in single lab
  8. 2012 High

    Multiple studies established the kinetic competition model of Sen1-dependent termination and extended it to human cells: Pol II elongation rate determines the window for Sen1-dependent termination; Sen1 interacts with Ser2-phosphorylated CTD supporting a handoff model of recruitment; and human SETX cooperates with Microprocessor/Xrn2/Rrp6 to induce Pol II pausing and premature termination.

    Evidence Pol II elongation rate mutants combined with sen1 mutants; two-hybrid/Co-IP/ChIP of Sen1–CTD-Ser2P; ChIP-seq and siRNA knockdown of SETX in human cells at HIV-1 and cellular loci

    PMID:22286094 PMID:22980978 PMID:23177741

    Open questions at the time
    • Whether human SETX functions in an NNS-equivalent complex was unknown
    • Direct Sen1-CTD binding stoichiometry and affinity were not quantified
  9. 2013 High

    Discovery that SETX is sumoylated and that sumoylation mediates interaction with the exosome subunit Rrp45 provided a mechanistic link between SETX and RNA degradation at DNA damage sites; AOA2 mutations specifically disrupt this interaction, distinguishing the AOA2 pathomechanism from ALS4.

    Evidence Co-IP of SETX–Rrp45, sumoylation assays, co-localization microscopy, disease mutation analysis

    PMID:24105744

    Open questions at the time
    • Whether sumoylation-dependent exosome recruitment is required for termination or only DNA damage response was unresolved
    • The E3 SUMO ligase responsible was not identified
  10. 2015 High

    Reconstitution of the S. cerevisiae Sen1 helicase domain confirmed 5′-to-3′ translocation, preferential RNA binding over DNA in the presence of ATP, and the ability to prevent R-loop formation in vitro, providing direct biochemical evidence for R-loop resolution activity.

    Evidence Recombinant Sen1 helicase domain; ATPase, unwinding, and EMSA assays

    PMID:26198638

    Open questions at the time
    • Full-length Sen1 regulation of helicase activity was not addressed
    • R-loop resolution on chromatinized templates was not tested
  11. 2017 High

    Two landmark studies resolved the structural basis and biochemical mechanism of Sen1-mediated termination: the crystal structure of the helicase core revealed a unique 'brace' for RNA binding and a 'prong' essential for 5′-to-3′ unwinding; reconstituted termination assays showed the helicase domain alone suffices to dissociate Pol II elongation complexes, favored by upstream DNA reannealing.

    Evidence 1.8 Å crystal structure of Sen1 helicase domain; in vitro transcription termination with purified elongation complexes and Sen1; mutagenesis of brace and prong

    PMID:28180347 PMID:28408439

    Open questions at the time
    • How the N-terminal regulatory domain modulates termination was unknown
    • Structural basis of the full-length protein was not available
  12. 2018 High

    Cell-cycle regulation of Sen1 abundance by ubiquitin-proteasome degradation demonstrated that precise Sen1 levels are critical for proper termination, and ALS4 mouse models showed that SETX gain-of-function mutations cause TDP-43 mislocalization, stress granule formation, and impaired nucleocytoplasmic transport, defining the ALS4 pathomechanism.

    Evidence Cell-cycle staging, NET-seq of Sen1 overexpression (yeast); transgenic and knock-in ALS4 mouse models with neuropathology and transport assays

    PMID:29656924 PMID:29725819

    Open questions at the time
    • The ubiquitin ligase targeting Sen1 for degradation was not identified
    • Whether TDP-43 mislocalization is a direct or indirect consequence of SETX mutation was unclear
  13. 2019 High

    Four studies refined the termination mechanism at atomic and single-molecule resolution: crystal structures of Sen1 NIM–Nrd1 CID complexes defined the physical basis of NNS assembly; single-molecule trapping revealed a transient half-rewound intermediate during termination; Pol II CTD Tyr1 phosphorylation was shown to promote NNS-dependent pausing; and fission yeast Sen1 was found to terminate RNA Pol III transcription independently of R-loop resolution.

    Evidence Crystal structures of three NIM–CID complexes; single-molecule magnetic trapping; CTD Tyr1 mutant genetic analysis; S. pombe sen1 deletion ChIP and RNA analysis

    PMID:30639244 PMID:30948716 PMID:31104813 PMID:31294478

    Open questions at the time
    • Whether the half-rewound intermediate occurs in vivo was not established
    • Pol III termination function of Sen1 in budding yeast or humans was not tested
  14. 2020 High

    Sen1's replication-associated function was separated from its transcription termination role: Sen1 associates with replisomes via Ctf4 and Mrc1, and a separation-of-function mutant (sen1-3) that loses replisome binding but retains termination activity shows increased genome instability; additionally, a CTD-mimetic motif in Sen1's disordered region enhances Pol II release via the Nrd1 CID.

    Evidence Co-IP of Sen1–Ctf4/Mrc1, sen1-3 separation-of-function mutant phenotyping, genome instability assays; NMR/crystal structure of CTD-mimetic motif with Nrd1 CID, in vitro termination assays

    PMID:32075754 PMID:32107786

    Open questions at the time
    • Whether human SETX similarly interacts with replisome components was unknown
    • How the CTD-mimetic motif is regulated in vivo was unresolved
  15. 2020 High

    Sen1/SETX was shown to limit DNA:RNA hybrid accumulation at DSBs, preventing aberrant Ku70-80 recruitment and mutagenic NHEJ/MMEJ; separately, SETX depletion was found to impair autophagy gene transcription and autophagic flux, including in AOA2 patient fibroblasts.

    Evidence ChIP and DRIP at HO-induced DSBs, genetic epistasis for DSB repair pathway choice; SETX siRNA, autophagy flux assays, patient fibroblast analysis

    PMID:32375052 PMID:32686621

    Open questions at the time
    • The autophagy phenotype was reported by a single lab and its relationship to R-loop resolution was unclear
    • Whether DSB-associated R-loop resolution requires SETX helicase activity or a scaffold function was not defined
  16. 2021 High

    The PERK/ATF4 unfolded protein response was identified as a transcriptional inducer of SETX during hypoxia, where SETX resolves R-loops to protect against DNA damage and maintain DNA replication, linking stress signaling to R-loop homeostasis.

    Evidence SETX knockdown in hypoxia; DRIP, DNA damage markers, replication rate assays; ATF4 pathway inhibition

    PMID:34140498

    Open questions at the time
    • Whether ATF4-mediated SETX induction occurs in non-hypoxic stress contexts was not tested
    • Direct ATF4 binding to the SETX promoter was not demonstrated
  17. 2022 High

    Genome-wide mapping using the sen1-3 separation-of-function mutant showed Sen1 removes Pol II at both transcription–replication and transcription–transcription conflicts, and that genomic instability requires simultaneous loss of replisome interaction, ncRNA termination, and R-loop removal; in human cells, SETX depletion causes chromosome fragility rescued by FANCD2-mediated mitotic DNA synthesis.

    Evidence High-resolution TRC/R-loop mapping with sen1 mutant combinations; SETX/FANCD2 co-depletion, DNA fiber and chromosome fragility assays

    PMID:35839782 PMID:36543851

    Open questions at the time
    • The relative contribution of each Sen1 function to total genome instability was not quantified
    • Whether FANCD2 synthetic lethality extends to in vivo models was untested
  18. 2023 High

    Cryo-EM and crystal structures of full-length Sen1 revealed an elongated inchworm architecture with an autoinhibitory N-terminal domain occluding the RNA-binding cleft, and the activated helicase bound to RNA/ADP-SO₄ implicated a single-nucleotide power stroke; AOA2 mutations impair RNA binding. Separately, Sen1 was shown to assist replication termination at TERs and telomeres alongside Rrm3.

    Evidence Cryo-EM of full-length Sen1; X-ray crystallography of Sen1Hel–RNA–ADP-SO₄; AOA2 mutation biochemistry; genetics and genome-wide replication mapping with sen1/rrm3 mutants, TEM

    PMID:37405920 PMID:37832548

    Open questions at the time
    • Mechanism of autoinhibition relief in vivo was not defined
    • Whether the N-terminal domain is regulated by post-translational modification was unknown
  19. 2024 High

    Single-molecule quantification of Sen1 translocation kinetics and prong-deletion analysis established that the prong subdomain maintains Sen1–Pol II interaction during termination and is required for efficient formation of the topological intermediate prior to Pol II dissociation.

    Evidence Single-molecule magnetic trapping of Sen1 translocation and termination; prong-deletion constructs

    PMID:38261990

    Open questions at the time
    • How the prong contacts the Pol II surface was not structurally resolved
    • Processivity measurements for full-length Sen1 (including the N-terminal domain) were not available
  20. 2025 High

    Reconstitution of SETX-mediated R-loop unwinding with BRCA1-BARD1 revealed that BRCA1-BARD1 stimulates SETX activity and overcomes RAD52-mediated inhibition, with Ser642 phosphorylation driving the SETX–BRCA1 BRCT interaction; separately, SETX was shown to prevent R-loop–driven hyper-resection at DSBs that otherwise activates break-induced replication through PCNA ubiquitination and PIF1.

    Evidence In vitro R-loop unwinding with purified SETX/BRCA1-BARD1/RAD52; phospho-mutant Co-IP and cellular R-loop/replication assays; SETX depletion with BIR factor epistasis and synthetic lethality

    PMID:41037402 PMID:41917467

    Open questions at the time
    • Whether BRCA1-BARD1 stimulation of SETX occurs at all R-loop sites or specifically at TRC-associated R-loops was not distinguished
    • The kinase phosphorylating SETX Ser642 was not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the mechanism by which SETX autoinhibition is relieved in vivo; the identity of the kinase(s) and E3 ubiquitin/SUMO ligase(s) regulating SETX activity and stability; whether a human NNS-equivalent complex exists; and a structural model of the SETX–Pol II termination complex.
  • No structure of the Sen1/SETX–Pol II termination complex exists
  • Human NNS-equivalent complex has not been identified
  • Kinases and ligases controlling SETX are unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140657 ATP-dependent activity 6 GO:0140098 catalytic activity, acting on RNA 5 GO:0003723 RNA binding 4 GO:0003677 DNA binding 2
Localization
GO:0005634 nucleus 2 GO:0005730 nucleolus 1
Pathway
R-HSA-74160 Gene expression (Transcription) 9 R-HSA-73894 DNA Repair 6 R-HSA-8953854 Metabolism of RNA 5 R-HSA-1640170 Cell Cycle 3 R-HSA-69306 DNA Replication 3 R-HSA-1643685 Disease 2
Partners
BRCA1CTF4EXOSC9MRC1NAB3NRD1RRM3
Complex memberships
NNS (Nrd1-Nab3-Sen1) complex

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 SETX encodes a 302.8-kDa protein containing a DNA/RNA helicase domain with strong homology to RENT1 and IGHMBP2, proteins involved in RNA processing; missense mutations (T3I, L389S, R2136H) in SETX cause ALS4, implicating helicase activity or RNA processing dysfunction in neuronal degeneration. Positional cloning, mutation identification, sequence homology analysis American journal of human genetics High 15106121
1999 The S. pombe Sen1 ortholog (SpSen1p) is an RNA and DNA helicase that unwinds RNA:DNA and DNA:RNA hybrid duplexes, hydrolyzes ATP in the presence of ribo- or deoxyribopolynucleotides, and translocates in the 5' to 3' direction. Biochemical purification, in vitro ATPase assay, helicase unwinding assay, partial amino acid sequencing Biochemistry High 10545196
1997 Yeast Sen1 is required for processing of diverse RNA classes including tRNAs, rRNAs, and snRNAs/snoRNAs; small nucleolar RNAs co-immunoprecipitate with Sen1; inactivation of the helicase domain impairs RNA processing. Temperature-shift experiments, RNA abundance comparison, co-immunoprecipitation of snoRNAs with Sen1 Nucleic acids research High 9365256
1992 Yeast Sen1 (SEN1) is required for endonucleolytic cleavage of introns from pre-tRNAs; Sen1 contains a leucine zipper, NTP-binding motifs, and a nuclear localization signal; the C-terminal 1,214 aa are essential; Sen1 shares ~500 aa homology with yeast UPF1. Genetic complementation, in vitro endonuclease assay, domain deletion analysis, sequence analysis Molecular and cellular biology High 1569945
1995 Sen1 localizes to the nucleus with a granular distribution; a putative NLS within Sen1 is necessary for nuclear targeting; inactivation of Sen1 causes mislocalization of nucleolar proteins Nop1 and Ssb1. Cell fractionation, immunofluorescent microscopy with Sen1-specific antibodies, temperature-shift experiments Molecular & general genetics High 8544822
2006 Sen1 helicase controls genome-wide RNA polymerase II distribution; a single amino acid substitution compromising Sen1 function causes profound changes in Pol II distribution over both noncoding and protein-coding genes, establishing Sen1 as a regulator of transcription. Genome-wide ChIP mapping of Pol II occupancy across entire yeast genome; comparison of wild-type vs. Sen1 mutant strains Molecular cell High 17157256
2008 Sen1 interacts with Nrd1 and Nab3 to form the NNS termination complex; Nrd1 contains a CID domain that preferentially binds Ser5-phosphorylated RNA Pol II CTD (the promoter-proximal form), explaining why NNS acts specifically at short Pol II-transcribed genes. Crystal structure of Nrd1 CID domain; CTD phosphopeptide binding assays Nature structural & molecular biology High 18660819
2011 Yeast Sen1 helicase restricts RNA:DNA hybrid (R-loop) formation during transcription; loss of Sen1 leads to R-loop accumulation and transcription-associated recombination; SEN1 genetically interacts with DNA repair genes, placing Sen1 in R-loop resolution coupled to homologous recombination. Genetic epistasis (SEN1 interaction with DNA repair mutants), in vivo R-loop detection, recombination assays Molecular cell High 21211720
2011 Mpk1 MAPK prevents Sen1-dependent premature transcription termination of stress-induced genes by interacting with the Paf1 subunit of the Paf1C elongation complex, blocking recruitment of the Sen1-Nrd1-Nab3 termination complex to elongating polymerase. Genetic epistasis, mutation analysis of Paf1 that blocks Mpk1 interaction, transcription elongation assays Cell High 21376235
2011 H3K4 trimethylation by Set1 promotes efficient NNS-dependent termination by facilitating appropriate recruitment of Nrd1; Set1 modulates histone acetylation in the promoter-proximal region via Rpd3L and NuA3 complexes, which affects kinetics of early Pol II elongation and NNS termination efficiency. Genetic interaction (set1Δ exacerbates nrd1 termination defects), ChIP analysis of Nrd1 recruitment Molecular and cellular biology Medium 21709022
2012 Kinetic competition between RNA Pol II elongation rate and Sen1 helicase activity establishes temporal and spatial window for early termination: faster-transcribing Pol II increases read-through at Sen1-dependent terminators, while slower Pol II suppresses sen1 termination defects. Genetic suppression/enhancement using Pol II elongation rate mutants combined with sen1 mutants; transcription readthrough assays Molecular cell High 23177741
2012 Human SETX (senataxin) cooperates with Microprocessor (Drosha/DGCR8), Xrn2, and Rrp6 to induce RNAPII pausing and premature termination at the HIV-1 promoter through cleavage of the stem-loop RNA TAR; SETX is recruited to cellular gene targets to modulate transcription elongation. ChIP-seq, ChIP, siRNA knockdown of SETX and other factors, transcription assays Cell High 22980978
2013 SETX is sumoylated, and sumoylation-dependent interaction between SETX and Rrp45 (exosome subunit) targets the exosome to sites of transcription-related DNA damage; AOA2 but not ALS4 mutations in SETX disrupt SETX sumoylation and the Rrp45 interaction. Co-immunoprecipitation of SETX with Rrp45, co-localization microscopy, sumoylation assays, patient mutation analysis Genes & development High 24105744
2013 Senataxin self-associates via its amino-terminal binding domain (dimerization); the L389S ALS4 mutation does not abrogate self-association; SETX undergoes ubiquitin and SUMO post-translational modifications. Yeast two-hybrid screen of human brain library with SETX as bait, Co-IP to confirm dimerization, Western blot for ubiquitin/SUMO PloS one Medium 24244371
2015 The S. cerevisiae Sen1 helicase domain (89 kDa) purified from E. coli binds single-stranded RNA and DNA, translocates in the 5' to 3' direction, and preferentially binds RNA over DNA in the presence of ATP; Sen1-HD can prevent stable RNA:DNA hybrid formation consistent with R-loop resolution. Recombinant protein purification, in vitro ATPase assay, helicase unwinding assay, electrophoretic mobility shift assay The Journal of biological chemistry High 26198638
2016 The N-terminal non-essential region of yeast Sen1 plays an important role in transcription-coupled DNA repair (TCR); unlike Rad26, Sen1 is required for efficient TCR at essentially all damaged sites in the transcribed strand, and the helicase activity of Sen1 is largely dispensable for TCR. Genetic analysis using sen1 truncation mutants and TCR repair assays; epistasis with spt4Δ Nucleic acids research Medium 27179024
2017 The Sen1 helicase domain alone is sufficient to dissociate the RNA Pol II elongation complex in vitro; Sen1 translocates along single-stranded RNA and DNA in the 5' to 3' direction and is a relatively poorly processive enzyme; Sen1 can promote forward translocation of stalled polymerases and dissociation of elongation complexes is favored by DNA reannealing upstream of RNAPII. In vitro transcription termination assay with reconstituted elongation complexes and purified Sen1 protein; biochemical translocation assays Nucleic acids research High 28180347
2017 Crystal structure of the ~90 kDa Sen1 helicase core (SF1B family) at 1.8 Å resolution reveals a unique 'brace' structural feature essential for RNA binding and unwinding, and a 'prong' (subdomain 1C) essential for 5'-3' unwinding and transcription termination in vitro; disease-associated senataxin mutations reduce RNA unwinding and impair transcription termination in vitro. X-ray crystallography, in vitro helicase assays, in vitro transcription termination assay, mutagenesis The EMBO journal High 28408439
2018 Sen1 levels increase during S and G2 phases of the cell cycle; Sen1 abundance is regulated by ubiquitin-proteasome-mediated degradation; overexpression of Sen1 leads to decreased ncRNA production and altered mRNA termination, demonstrating that precise Sen1 levels are critical for proper termination. Cell cycle staging, Western blot for Sen1 levels, NET-seq analysis of overexpression effects, proteasome inhibition assays Molecular cell High 29656924
2019 Crystal structures of three Sen1 Nrd1-interaction motifs (NIMs) bound to the Nrd1 CID domain reveal direct physical interactions; removal of all three NIMs abolishes NNS complex formation and causes ncRNA termination defects in yeast. Crystal structure determination, in vitro binding assays, yeast genetic assays with NIM-deletion mutants Structure High 31104813
2019 Single-molecule magnetic trapping assays reveal that Sen1-induced Pol II termination proceeds through a transient intermediate in which the Pol II transcription bubble appears half-rewound, requiring ~40 sec to form and lasting ~20 sec prior to final Pol II dissociation. Single-molecule magnetic-trapping assay with real-time monitoring of transcription bubble rewinding Nature communications High 30948716
2019 RNA Pol II CTD Tyrosine 1 phosphorylation is required for efficient termination by the Nrd1-Nab3-Sen1 (NNS) pathway; Tyr1 promotes pausing at the 5' end of genes and slowing transcription suppresses termination defects caused by Tyr1 mutation. CTD Tyr1 phosphosite mutations, transcription termination assays, suppression by slow Pol II mutations Molecular cell High 30639244
2019 Fission yeast Sen1 promotes efficient transcription termination by RNA Pol III in vivo; loss of Sen1 causes RNAP3 accumulation downstream of RNAP3-transcribed genes and 3'-extended transcripts, independently of R-loop removal. ChIP, RNA analysis, Sen1 deletion phenotype analysis; R-loop removal genetic controls The EMBO journal High 31294478
2020 Sen1 associates with replisomes via its N-terminus through interaction with Ctf4 and Mrc1 replisome components; separation-of-function mutant sen1-3 abolishes replisome binding without affecting transcription termination and shows increased genome instability and recombination; RNH1 overexpression suppresses sen1-3 RNA metabolism defects but not checkpoint defects. Co-immunoprecipitation of Sen1 with replisome components, generation of separation-of-function mutant, genome instability assays, epistasis with checkpoint and RNA metabolism mutants Cell reports High 32075754
2020 Sen1, the yeast ortholog of SETX, is recruited to HO-induced double-strand breaks and limits DNA:RNA hybrid accumulation at DSBs; in the absence of Sen1, hybrid accumulation promotes Ku70-80 binding, mutagenic NHEJ, MMEJ, and chromosome translocations; DNA:RNA hybrids, Mre11, and Dna2 initiate a non-canonical resection mechanism. ChIP at induced DSBs, DRIP (DNA:RNA hybrid IP), genetic assays for NHEJ/MMEJ/HDR fidelity, epistasis analysis Cell reports High 32375052
2020 A motif in an intrinsically disordered region of Sen1 mimics the phosphorylated CTD of RNAPII and is recognized by the Nrd1 CID domain; the Sen1 N-terminal domain interaction with the CTD enhances Sen1 capacity to induce release of paused RNAPII but does not promote initial Sen1 recruitment. Structural characterization of Sen1-CTD mimetic motif by NMR/crystallography; in vitro termination assays with Sen1 CTD-interaction mutants The EMBO journal High 32107786
2020 SETX depletion inhibits autophagy progression, leading to accumulation of ubiquitinated proteins, decreased clearance of protein aggregates, and mitochondrial defects; SETX directly affects transcription of autophagy genes; AOA2 patient fibroblasts also show perturbation of the autophagy pathway. SETX siRNA knockdown, autophagy flux assays, protein aggregate quantification, mitochondrial function assays, patient fibroblast analysis Autophagy Medium 32686621
2021 SETX induction in hypoxia is regulated by the PERK/ATF4 arm of the unfolded protein response; hypoxia-induced SETX resolves R-loops to protect cells from DNA damage and maintains DNA replication rates in hypoxic conditions. SETX knockdown in hypoxia, R-loop detection (DRIP), DNA damage markers, replication rate assays, ATF4 pathway inhibition Nature communications High 34140498
2022 Sen1 removes RNA Pol II at transcription-replication conflicts (TRCs) within genes and at sites of transcription-transcription conflicts under physiological conditions; genomic instability requires simultaneous loss of Sen1 replisome interaction, ncRNA termination, and R-loop removal. High-resolution genome-wide mapping of TRCs and R-loops using Sen1 separation-of-function mutant; genetic combination experiments Molecular cell High 35839782
2022 SETX depletion causes spontaneous under-replication and chromosome fragility due to transcription and R-loops that persist in mitosis; FANCD2 promotes mitotic DNA synthesis via XPF and MUS81 endonucleases to rescue SETX deficiency; SETX and FANCD2 are synthetic lethal in cancer cells. Co-depletion of SETX and FANCD2, DNA fiber assays, mitotic DNA synthesis assays, chromosome fragility assays, endonuclease mutant epistasis Communications biology High 36543851
2023 Cryo-EM structures of Sen1 reveal an elongated inchworm-like architecture with an N-terminal helical repeat regulatory domain (Sen1N) flexibly linked via an intrinsically disordered tether to the C-terminal SF1B helicase core (Sen1Hel); the Sen1N domain promotes autoinhibition by occluding the RNA substrate-binding cleft; X-ray structure of activated Sen1Hel engaging single-stranded RNA and ADP-SO4 implicates a single-nucleotide power stroke in RNA translocation; AOA2 disease mutations impair RNA binding. Cryo-EM structural determination, X-ray crystallography of helicase domain with RNA/ADP-SO4, biochemical RNA binding and helicase assays, AOA2 mutation analysis Molecular cell High 37832548
2012 Sen1 interacts directly with the Ser2-phosphorylated form of the RNA Pol II CTD; a sen1-R302W mutation impairing this interaction reduces occupancy of Sen1 across noncoding genes by ChIP, and across early and late but not mid-coding gene regions, supporting a handoff model of CTD-phosphorylation-dependent recruitment. Two-hybrid analysis, immunoprecipitation, chromatin immunoprecipitation of Sen1 across gene targets Eukaryotic cell Medium 22286094
2025 Full-length SETX unwinds R-loops with broad specificity; BRCA1-BARD1 binds R-loops and stimulates R-loop unwinding by SETX; BRCA1-BARD1 alleviates inhibitory effect of RAD52 on SETX-mediated R-loop unwinding; phosphorylation of SETX Ser642 promotes SETX-BRCA1 interaction via BRCA1 tandem BRCT domain; mutations in SETX catalytic domain or Ser642 lead to R-loop accumulation, transcription-replication conflicts, and DSBs. In vitro R-loop unwinding assays with purified SETX and BRCA1-BARD1; Co-IP; phospho-mutant analysis; cellular R-loop detection; replication fork assays Nature structural & molecular biology High 41917467
2024 Single-molecule experiments quantify Sen1 translocation on ssDNA: high translocation rates, processivity, and ATP affinity; deletion of the prong subdomain reduces termination efficiency and formation of the topological intermediate prior to termination, implicating the prong in maintaining interaction with the Pol II complex during termination. Single-molecule magnetic trapping assays of Sen1 translocation and termination; domain deletion constructs Nucleic acids research High 38261990
2018 ALS4 SETX mutations (R2136H and L389S) cause motor neuron degeneration in mice with nuclear clearing and cytosolic mislocalization of TDP-43, enhanced stress granule formation, nuclear membrane abnormalities (Ran/RanGAP1), and delayed nuclear import in cortical neurons. Transgenic and knock-in mouse models, neuropathological immunostaining, nucleocytoplasmic transport assays, stress granule quantification Acta neuropathologica High 29725819
2025 In SETX-deficient cells, R-loop/hybrid accumulation at double-ended DSBs triggers hyper-end resection requiring RAD52 and XPF; accumulated RNA/DNA hybrids on ssDNA overhangs stall Polα-primase-initiated fill-in synthesis, inducing PCNA ubiquitination and PIF1 loading to activate break-induced replication (BIR); SETX is synthetic lethal with PIF1, RAD52, and XPF. SETX depletion, genetic epistasis with BIR factors, PCNA ubiquitination assays, PIF1 ChIP, synthetic lethality assays Cell reports High 41037402
2023 Rrm3 and Sen1 helicases assist replication termination at TERs; Sen1 specifically acts at telomeres; Sen1 accumulates RNA Pol II at TERs and telomeres; double mutant sen1 rrm3 shows RNA-DNA hybrid accumulation and reversed/gapped converging forks; Rrm3 and Sen1 restrain Top1 and Top2 activities to prevent toxic positive supercoil accumulation. Genetics, genome-wide replication mapping, transmission electron microscopy, RNA-DNA hybrid detection, topoisomerase activity analysis Cell reports High 37405920

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). American journal of human genetics 642 15106121
2011 Yeast Sen1 helicase protects the genome from transcription-associated instability. Molecular cell 304 21211720
2006 Genome-wide distribution of yeast RNA polymerase II and its control by Sen1 helicase. Molecular cell 268 17157256
2008 The Nrd1-Nab3-Sen1 termination complex interacts with the Ser5-phosphorylated RNA polymerase II C-terminal domain. Nature structural & molecular biology 238 18660819
2012 Microprocessor, Setx, Xrn2, and Rrp6 co-operate to induce premature termination of transcription by RNAPII. Cell 149 22980978
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