Affinage

SNRNP200

U5 small nuclear ribonucleoprotein 200 kDa helicase · UniProt O75643

Length
2136 aa
Mass
244.5 kDa
Annotated
2026-04-28
60 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SNRNP200 (hBrr2) is a Ski2-like DEXH-box RNA helicase and permanent U5 snRNP component that drives spliceosome activation by ATP-dependent unwinding of the U4/U6 snRNA duplex, a prerequisite for catalytic core formation (PMID:9705931, PMID:9539711). The enzyme contains two tandem Hel308-like helicase cassettes: only the N-terminal cassette is catalytically active, while the C-terminal cassette binds nucleotides and allosterically modulates unwinding through long-range intercassette communication and orientation-dependent stimulation or inhibition (PMID:23045696, PMID:34048711, PMID:31914407). Multiple regulatory mechanisms converge on Brr2, including autoinhibition by its N-terminal region, inhibition by insertion of the Prp8 Jab1/MPN C-terminal tail into the RNA-binding tunnel, competition by the Prp8 RNase H domain for the U4 snRNA loading site, and modulation by trans-acting factors (FBP21, Ntr2, C9ORF78) that bind the C-terminal cassette (PMID:26637280, PMID:23704370, PMID:23124066, PMID:28838205, PMID:35241646). Retinitis pigmentosa-causing missense mutations in the ratchet helix (S1087L, R1090L) specifically impair RNA translocation and unwinding without disrupting tri-snRNP assembly, leading to aberrant splice-site selection (PMID:19878916, PMID:27072132, PMID:24302620).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1998 High

    Identification of the U4/U6 unwinding activity resolved which snRNP subunit drives spliceosome activation: both yeast Brr2 and human U5-200kD were shown to catalyze ATP-dependent U4/U6 duplex disruption, establishing the core enzymatic function of SNRNP200.

    Evidence Immunopurified native snRNP complex unwinding assays with helicase-dead mutant (yeast); purified U5-200kD from HeLa U5 snRNPs (human)

    PMID:9539711 PMID:9705931

    Open questions at the time
    • Substrate specificity and loading mechanism on U4/U6 not yet defined
    • Role of other U5 snRNP proteins in regulating unwinding unknown
  2. 2008 High

    Discovery that Prp8's C-terminal region simultaneously stimulates U4/U6 unwinding while inhibiting ATPase activity established that Brr2 is subject to complex trans-regulation by its stable binding partner, and linked retinitis pigmentosa-associated Prp8 mutations to defective Brr2 regulation.

    Evidence In vitro unwinding and ATPase assays with purified Prp8 fragments; RP allele testing in yeast

    PMID:19098916

    Open questions at the time
    • Molecular basis of dual stimulation/inhibition not structurally resolved
    • How Prp8 regulation is switched on/off during the splicing cycle unknown
  3. 2009 High

    Crystal structures of Brr2 Sec63 domains revealed a dual Hel308-like module architecture and showed that the C-terminal module mediates Prp8/Snu114 interaction, while RP mutations S1087L and R1090L in the ratchet helix of the first Sec63 domain specifically impair U4/U6 unwinding without disrupting tri-snRNP assembly, pinpointing the disease mechanism.

    Evidence Crystal structures; rational mutagenesis; U4/U6 unwinding and tri-snRNP assembly assays in yeast and human systems

    PMID:19525970 PMID:19716790 PMID:19878916

    Open questions at the time
    • Full-length Brr2 structure not yet available
    • Translocation mechanism along U4 snRNA not defined
  4. 2012 High

    Structural and functional analysis of full dual-cassette Brr2 revealed that only the N-terminal cassette is catalytically active while the C-terminal cassette acts as a regulatory cofactor, and separately showed that Prp8's RNase H domain blocks Brr2 loading onto U4 snRNA, defining two layers of Prp8-mediated inhibition.

    Evidence Crystal structures of dual-cassette Brr2; mutagenesis of intercassette interface and ATP pocket; cross-linking/MS mapping of Prp8 RH–U4/U6 contacts; RNA binding and unwinding assays

    PMID:23045696 PMID:23124066

    Open questions at the time
    • How the two Prp8 inhibitory mechanisms (RH domain and Jab1 tail) are coordinated temporally unknown
    • Nucleotide occupancy states of C-terminal cassette during splicing not determined
  5. 2013 High

    Crystal structures of the Prp8 Jab1/MPN domain bound to Brr2 revealed a direct inhibitory mechanism—the Jab1 C-terminal tail inserts into Brr2's RNA-binding tunnel, competing with substrate—and showed that RP-linked Prp8 mutations weaken this inhibition; concurrently, Sad1 was shown to counteract premature Brr2-mediated tri-snRNP disruption, and RP Brr2 mutations were found to alter splice-site selection in human cells.

    Evidence Co-crystal structures of Brr2–Jab1 (human and yeast); ATPase/unwinding assays; tri-snRNP dissociation assays; knockdown-rescue with RP mutants in human cells

    PMID:23704370 PMID:23727230 PMID:24190974 PMID:24302620

    Open questions at the time
    • Mechanism by which Jab1 tail is withdrawn to activate Brr2 in the spliceosome unknown
    • Whether Sad1 directly contacts Brr2 or acts indirectly not resolved
  6. 2015 High

    The ~500-residue N-terminal region of Brr2 was shown to act as a cis-autoinhibitory element that clamps the two helicase cassettes, competes with dsRNA substrate, and is required beyond U4/U6 unwinding for retaining U5 and U6 snRNAs during spliceosome activation.

    Evidence Crystal structure of full-length Brr2–Jab1 complex; N-terminal truncation mutants assayed for RNA binding, ATPase, helicase activity, and spliceosomal complex composition in vivo

    PMID:25670679 PMID:26637280

    Open questions at the time
    • How N-terminal autoinhibition is relieved during the B-to-Bact transition not determined
    • Identity of signals triggering relief of autoinhibition unknown
  7. 2016 High

    Mechanistic dissection established that Brr2 translocates only a limited distance on U4 snRNA and relies on U6 snRNA conformational rearrangement (substrate-assisted unwinding) to complete U4/U6 disruption; separately, RP ratchet-helix mutations were shown to impair translocation specifically, and dual autoinhibition by the N-terminal region and Jab1 tail was shown to target dsRNA vs ssRNA accommodation differentially.

    Evidence Reconstituted U4/U6 di-snRNP disruption with recombinant components; systematic biochemical characterization of RP mutants; crystal structures from two organisms with truncation/mutant RNA binding studies

    PMID:27072132 PMID:27454531 PMID:27880071

    Open questions at the time
    • Step-size and processivity of Brr2 translocation not quantified
    • Whether substrate-assisted mechanism operates in the context of the full spliceosome not tested
  8. 2017 High

    Trans-regulators binding the C-terminal cassette were identified: FBP21 uses an intrinsically disordered region to allosterically inhibit Brr2, while small-molecule inhibitors targeting both allosteric and active sites were co-crystallized, validating druggability of the intercassette interface.

    Evidence SPR, analytical SEC, peptide SPOT analysis, unwinding assays (FBP21); HTS and co-crystal structures (inhibitors)

    PMID:28586220 PMID:28838205

    Open questions at the time
    • In vivo functional consequence of FBP21-mediated inhibition not demonstrated
    • Selectivity and efficacy of inhibitors in splicing-dependent cellular assays not shown
  9. 2019 High

    Engineered disulfide bridges locking the two cassettes in distinct relative orientations demonstrated that intercassette rotation can either stimulate or inhibit unwinding, establishing that the C-terminal cassette acts as a conformational switch rather than a simple stimulator.

    Evidence Crystal structure of BRR2–Prp8 activating domain; disulfide-locked variants; ATPase and helicase assays

    PMID:31914407

    Open questions at the time
    • Which cassette orientation is adopted at each spliceosomal stage not mapped
    • Whether intercassette rotation is actively driven or passive unknown
  10. 2021 High

    Nucleotide-binding measurements revealed that the C-terminal cassette binds ADP >100-fold more tightly than the N-terminal cassette, and long-range allosteric communication across the intercassette interface was demonstrated: disrupting nucleotide binding at the C-terminal cassette reduced affinity at the N-terminal cassette 70 Å away.

    Evidence Biophysical nucleotide binding assays; intercassette interface mutations; molecular dynamics simulations

    PMID:34048711

    Open questions at the time
    • Identity of the allosteric pathway residues at atomic resolution incomplete
    • Whether ADP/ATP exchange at the C-terminal cassette occurs during the splicing cycle unknown
  11. 2022 High

    Cryo-EM structures of C9ORF78 and FBP21 bound to Brr2's C-terminal cassette identified a shared, mutually exclusive regulatory site ('multi-factor trafficking site'), and C9ORF78 knockdown produced BRR2-dependent splicing changes including alternative 3'-splice-site usage, establishing the C-terminal cassette as a regulatory hub for sequential trans-factor engagement.

    Evidence Cryo-EM structures; affinity purification/MS; RNA UV-crosslinking; knockdown with splicing analysis

    PMID:35241646

    Open questions at the time
    • Order of factor exchange at the C-terminal cassette during splicing cycle not resolved
    • Whether additional factors share this binding surface unknown
  12. 2025 High

    iCLIP mapping of RP mutant Brr2 in living cells showed broadened binding on U4 snRNA upstream of stem I, directly demonstrating impaired translocation in vivo; separately, Brr2 was identified as a repressor of circRNA-associated R-loops (ciR-loops), with loss of function causing R-loop accumulation, DNA damage, and replication defects.

    Evidence iCLIP in HeLa/RPE cells plus FRAP and in vitro helicase assays (RP mutations); loss-of-function genetics with R-loop detection and DNA damage assays (ciR-loop role)

    PMID:40045025 PMID:41093835

    Open questions at the time
    • Whether the ciR-loop repression function requires Brr2's helicase activity or is independent unknown
    • Cell-type specificity of RP mutant translocation defects not fully explored

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple inhibitory and stimulatory inputs on Brr2 (N-terminal autoinhibition, Prp8 RH domain, Prp8 Jab1 tail, C-terminal cassette orientation, and trans-factors at the C-terminal cassette) are temporally coordinated across spliceosomal stages to achieve precisely timed activation and subsequent disassembly remains unresolved.
  • Time-resolved single-molecule studies of Brr2 regulation during a complete splicing cycle are lacking
  • Whether Brr2's non-splicing roles (innate immunity, ciR-loop resolution) share the same regulatory architecture is unknown
  • Structural basis for how the N-terminal PWI-like domain engages downstream spliceosomal factors during activation not determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 5 GO:0140098 catalytic activity, acting on RNA 5 GO:0140657 ATP-dependent activity 5
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 1
Pathway
R-HSA-8953854 Metabolism of RNA 9 R-HSA-1643685 Disease 4
Partners
C9ORF78FBP21NTR2PRPF8SAD1SNU114SPF27
Complex memberships
U4/U6.U5 tri-snRNPU5 snRNP

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Brr2 (yeast ortholog of SNRNP200) unwinds the U4/U6 RNA duplex in an ATP hydrolysis-dependent manner; immunopurified Brr2 in a native U1/U2/U5/U4/U6 snRNP complex catalyzes U4/U6 base-pair disruption and release of free U4 and U6 snRNPs, and a helicase-domain mutation (brr2-1) abolishes this activity. Immunopurification of native snRNP complex, ATP hydrolysis assay, helicase-domain point mutant Current biology : CB High 9705931
1998 The human U5-200kD protein (SNRNP200/hBrr2) is the subunit of U5 snRNP responsible for ATP-dependent unwinding of U4/U6 RNA duplexes in vitro; activity was traced to the purified 200kD DEXH-box protein after high-salt depletion of U5-100kD from U5 snRNPs. In vitro U4/U6 RNA unwinding assay with purified HeLa U5 snRNPs; high-salt protein depletion; ion-exchange purification of U5-200kD to homogeneity Proceedings of the National Academy of Sciences of the United States of America High 9539711
2008 ATP-dependent Brr2-mediated dissociation of U4/U6 snRNAs in vitro is stimulated by the C-terminal region of the U5 snRNP protein Prp8 (Prp8-CTR); in contrast, Prp8-CTR simultaneously inhibits U4/U6-dependent ATPase activity; retinitis pigmentosa-linked prp8 alleles fail to stimulate Brr2 unwinding activity. In vitro U4/U6 unwinding and ATPase assays with purified Prp8 fragments; yeast genetics with RP alleles Nature structural & molecular biology High 19098916
2008 Brr2, Prp8, and the GTPase Snu114 are localized within distinct domains of the yeast tri-snRNP by electron microscopy: Brr2 occupies a 'head' domain, U4/U6 snRNP forms an 'arm' domain, and Prp8/Snu114 are central; the head and arm adopt variable relative positions suggesting dynamics during activation. Electron microscopy of genetically tagged tri-snRNP complexes; EM projection structure Nature structural & molecular biology Medium 18953335
2009 Crystal structure of the second Sec63 domain of Brr2 reveals structural similarity to domains 4-5 of DNA helicase Hel308; together with sequence conservation in RecA-like domains, this defines two consecutive Hel308-like modules (Hel308-I and -II) in Brr2; the C-terminal Hel308-II module (Hel308-II) interacts with Prp8 and Snu114 in vitro and in vivo, and Prp8-CTR facilitates binding of the Brr2-Prp8 complex to U4/U6. Crystal structure determination; in vitro and in vivo interaction assays; mutagenesis coupled with U4/U6 unwinding assays Nature structural & molecular biology High 19525970
2009 Crystal structures of the C-terminal Sec63 unit of yeast Brr2 reveal three domains, two of which resemble functional modules of the DNA helicase Hel308; rational mutagenesis and structural modeling show how RecA-like domains and the Sec63 unit form a functional entity mediating unidirectional and processive RNA duplex unwinding. Crystal structure determination; rational mutagenesis; splicing and U4/U6 di-snRNA unwinding assays Molecular cell High 19716790
2009 RP-linked mutations S1087L and R1090L in SNRNP200 reside in the ratchet helix of the first Sec63 domain and cause marked defects in U4/U6 snRNA unwinding without affecting U4/U6-U5 snRNP assembly, establishing that hBrr2's RNA unwinding activity is specifically impaired by these mutations. Yeast functional assays of analogous mutations (N1104L and R1107L in yeast Brr2p); U4/U6 unwinding assays; U4/U6-U5 tri-snRNP assembly assays American journal of human genetics High 19878916
2012 Human Brr2 contains two ring-like helicase cassettes that intimately interact; only the N-terminal cassette harbors ATPase and helicase activity in isolation, while the C-terminal cassette binds ATP and strongly stimulates the N-terminal helicase; structural features suggest Brr2 loads onto an internal region of U4/U6 di-snRNA via the N-terminal cassette. Crystal structures; mutagenesis of intercassette interface and C-terminal ATP pocket; RNA-binding and ATPase assays; functional complementation Proceedings of the National Academy of Sciences of the United States of America High 23045696
2012 The RNase H-like (RH) domain of Prp8 binds U4/U6 snRNA at single-stranded regions of U4 and U6 preceding U4/U6 stem I, and blocks Brr2's interaction with the same U4 single-stranded region, thereby inhibiting U4/U6 unwinding; cross-linking/mass spectrometry identifies the RH domain residues contacting U4/U6 snRNA. RNA binding assays; cross-linking coupled with mass spectrometry; U4/U6 unwinding assays with Prp8 RH domain Genes & development High 23124066
2013 The C-terminal tail of Prp8 (Jab1/MPN domain) inserts into Brr2's RNA-binding tunnel, directly competing with RNA substrate binding and thereby reversibly inhibiting Brr2's RNA-binding, ATPase, and U4/U6 unwinding activities; RP-linked Prp8 mutations in the C-terminal tail result in inefficient Brr2 repression. Crystal structure of Brr2–Prp8 C-terminal tail complex; ATPase assays; RNA-binding assays; U4/U6 unwinding assays Science (New York, N.Y.) High 23704370
2013 The Jab1/MPN domain of Prp8 binds exclusively to the N-terminal helicase cassette of yeast Brr2 and stimulates its activity; RP-causing mutations in the Prp8 Jab1/MPN domain are at or near the Brr2 interface; in U5 snRNP biogenesis, Brr2 replaces the assembly factor Aar2 after nuclear import, explaining their mutual exclusivity. Crystal structure of yeast Brr2–Prp8 Jab1/MPN complex; mutagenesis; biochemical competition assays Structure (London, England : 1993) High 23727230
2013 RP-linked mutations S1087L and R1090L in human BRR2 (SNRNP200) enhance cryptic splice-site recognition and impair proper 5'-splice-site selection; depletion of endogenous BRR2 enhanced usage of a β-globin cryptic splice site, which was restored by wild-type but not RP mutant BRR2. Stable expression of BAC-recombineered BRR2 mutants in human cell culture; RT-PCR splice-site usage assays; BRR2 knockdown-rescue experiments Human mutation Medium 24302620
2013 Sad1 counteracts Brr2-mediated ATP-dependent dissociation of the U4/U6•U5 tri-snRNP, maintaining tri-snRNP integrity; in the absence of Sad1, Brr2 drives tri-snRNP dissociation into U5 and U4/U6 snRNPs upon ATP hydrolysis. In vitro tri-snRNP dissociation assay with ATP; yeast genetics; sedimentation analyses Molecular and cellular biology High 24190974
2013 U5 snRNA internal loop 1 (IL1) serves as a binding platform for Prp8, Snu114, and Brr2 during U5 snRNP assembly; mutations in both sides of IL1 reduce association of all three proteins with U5 snRNA, and genetic interactions between brr2 alleles and U5 IL1 mutants reveal synthetic lethality. Yeast in vivo mutagenesis of U5 snRNA; co-immunoprecipitation; genetic synthetic lethality screening Journal of cellular biochemistry Medium 23857713
2015 The N-terminal region (~500 residues) of Brr2 encompasses two folded domains and adjacent linear elements that clamp and interconnect the helicase cassettes; it autoinhibits Brr2 via substrate competition and conformational clamping, and is required for stable Brr2 association with tri-snRNP and retention of U5 and U6 snRNAs during spliceosome activation in vivo. Crystal structure of full-length Brr2 with Prp8 Jab1/MPN domain; cross-linking/mass spectrometry; yeast growth and splicing assays with N-terminal truncations; RNA-binding, ATPase, and helicase assays Genes & development High 26637280
2015 The N-terminal region of Brr2 contains a noncanonical PWI-like domain that does not bind nucleic acids but instead interacts with other spliceosomal proteins including the Prp19 complex protein SPF27, supporting a role of the N-terminal region as a protein-protein interaction platform. Crystal structure of C. thermophilum Brr2 PWI-like domain; CD spectroscopy; yeast two-hybrid screen against human spliceosomal proteins; band-shift assays Acta crystallographica. Section D, Biological crystallography Medium 25849387
2015 The N-terminal domain of Brr2 (first ~120 residues) is required for spliceosomal activation beyond U4/U6 unwinding, specifically for retaining U5 and U6 snRNPs during activation; Brr2-Δ120 integrates into tri-snRNP and B complex but fails to maintain U5/U6 during Bact complex formation. Yeast genetics; yeast growth and splicing assays with N-terminal deletions; spliceosomal complex purification and snRNA composition analysis Nucleic acids research Medium 25670679
2016 During Brr2-mediated U4/U6 di-snRNP disruption, Brr2 translocates only a limited distance on the U4 snRNA strand; completion of unwinding requires U6 snRNA to adopt an alternative conformation, releasing Prp3 from U4/U6 di-snRNA while leaving Prp31 and Snu13 bound to U4 snRNA as an intact particle; Brr2 thus strips U6 of all precatalytic binding partners via a substrate-assisted mechanism. Recombinant in vitro Brr2-mediated U4/U6 di-snRNP disruption system; sequential protein addition assays; mutational analysis of U4/U6 di-snRNA conformation Proceedings of the National Academy of Sciences of the United States of America High 27354531
2016 SNRNP200 relocalizes into TBK1-containing cytoplasmic structures upon viral infection; its N-terminal Sec63 domain (Sec63-1) binds viral RNA and interacts with TBK1, promoting IRF3 activation and antiviral IFN-β production; the RP-linked S1087L mutant fails to relocalize and cannot rescue antiviral response in knockdown cells. Knockdown and rescue assays; co-immunoprecipitation with TBK1; RNA binding assays; live-cell imaging of localization upon infection; IFN-β production assays in patient PBMCs PLoS pathogens Medium 27454487
2016 RP mutations in the ratchet helix of Brr2 (S1087L, R1090L and analogues) exhibit a gradient of weakened RNA binding, reduced helicase activity, and reduced ATPase activity; the Prp8 Jab1/MPN domain increases wild-type Brr2 RNA binding and ATPase activity but does not differentially rescue RP mutants; RP mutant Brr2 proteins capable of RNA binding cannot fully unwind even short duplexes, suggesting impaired translocation. In vitro biochemical assays (RNA binding, ATPase, helicase) with purified RP-mutant Brr2 proteins; Prp8 Jab1 domain stimulation assays The Journal of biological chemistry High 27072132
2016 Brr2 autoinhibition (via N-terminal region) and Jab1-mediated inhibition (via Prp8 C-terminal tail insertion into RNA-binding tunnel) act in concert; the N-terminal region influences how the Jab1 tail interacts at the RNA-binding tunnel; N-terminal region specifically interferes with accommodation of double-stranded RNA, while the Jab1 tail interferes with single-stranded RNA, and regulation from the N-terminal region requires the inactive C-terminal helicase cassette. Crystal structures of S. cerevisiae and C. thermophilum Brr2-Jab1 complexes; systematic RNA binding and unwinding studies with truncation and mutant variants Cell cycle (Georgetown, Tex.) High 27880071
2017 FBP21 uses an intrinsically disordered C-terminal region to bind the C-terminal Sec63 unit of Brr2, allosterically inhibiting Brr2 helicase activity; direct interaction of FBP21 with U4/U6 di-snRNA further reduces the pool of unwound U4/U6 di-snRNA. Yeast two-hybrid; analytical SEC; surface plasmon resonance; peptide SPOT analysis; RNA binding and unwinding assays Nucleic acids research High 28838205
2017 Two distinct small-molecule inhibitors of Brr2 were identified: one binds an allosteric site between the C-terminal and N-terminal helicase cassettes and is Brr2-selective, and another binds the RNA-binding site inside the N-terminal cassette; co-crystal structures revealed binding modes. HTS ATPase assay; co-crystal structures; helicase inhibition assays; selectivity profiling Journal of medicinal chemistry High 28586220
2018 Ntr2, an intrinsically disordered yeast spliceosomal disassembly factor, binds via its N-terminal region to the C-terminal helicase unit of Brr2 and downregulates Brr2 helicase activity in vitro by modulating the fraction of helicase molecules productively bound to RNA substrate. CD spectroscopy; DLS; NMR spectroscopy; peptide SPOT analyses; analytical SEC; SPR; RNA binding and unwinding assays Biophysical journal High 29490241
2019 The inactive C-terminal cassette of BRR2 can both stimulate and inhibit the RNA-unwinding activity of the N-terminal cassette depending on the relative orientation of the two cassettes; engineered disulfide bridges locking cassettes in two different orientations had opposite effects (one enhancing, one inhibiting) on RNA unwinding and ATP hydrolysis. Crystal structure of BRR2 with Prp8 activating domain at 2.4 Å; engineered disulfide bridges; RNA unwinding and ATPase assays; comparison with spliceosomal cryo-EM structures The Journal of biological chemistry High 31914407
2021 Both BRR2 cassettes bind adenine nucleotides with high specificity; the inactive C-terminal cassette binds ADP >100-fold more tightly than the active N-terminal cassette; abrogation of nucleotide binding at the C-terminal cassette reduces nucleotide affinity at the N-terminal cassette 70 Å away via long-range allosteric communication mediated primarily across the intercassette interface. Biophysical nucleotide binding assays; mutations at intercassette surfaces; molecular dynamics simulations The Journal of biological chemistry High 34048711
2022 C9ORF78 tightly interacts with BRR2 at a multi-factor trafficking site on the C-terminal helicase cassette, occupying a binding surface that FBP21 also uses in a mutually exclusive manner; cryo-EM structures reveal how C9ORF78 and FBP21 wrap around the C-terminal helicase cassette; C9ORF78 knockdown leads to alternative NAGNAG 3'-splice site usage and BRR2-dependent exon skipping. Cryo-EM structures; in vitro binding assays; affinity purification/mass spectrometry; RNA UV-crosslinking; knockdown with alternative splicing analysis Nature communications High 35241646
2022 A C. elegans forward genetic screen identified a suppressor allele in SNRNP200/BRR2 (N18K at the unstructured N-terminus) that suppresses 5'-splice-site identity defects, revealing a conserved role for SNRNP200 in maintaining 5'-splice-site identity during spliceosome assembly. Forward genetic screen in C. elegans; mRNA-seq; double-mutant analysis; mapping of suppressor residues on cryo-EM spliceosome structures Nucleic acids research Medium 36321655
2024 Glucose-induced acetylation of SNRNP200 at K1610 prevents its proteasomal degradation; stabilized SNRNP200 then facilitates splicing of metabolic enzyme-encoding pre-mRNAs (GAPDH, ALDOA, GSS), increasing lactic acid and glutathione production in triple-negative breast cancer. Mass spectrometry identification of acetylation site; proteasome inhibition/ubiquitination assays; splicing assays; metabolic readouts Cell discovery Medium 39285160
2025 RP-linked mutations S1087L and R1090L in SNRNP200 broaden its binding profile on U4 snRNA upstream of U4/U6 stem I as measured by iCLIP, indicating impaired snRNA unwinding activity; this was confirmed by FRAP measurements and in vitro helicase activity assays comparing mutant and wild-type protein. iCLIP in HeLa and RPE cells; FRAP; in vitro helicase activity assays Cellular and molecular life sciences : CMLS High 40045025
2025 Y4 RNA fragment (YF1) binds to SNRNP200 and reduces its ubiquitination, stabilizing SNRNP200, which in turn enhances IL-10 pre-mRNA splicing in macrophages; this effect is reversed by a specific SNRNP200 inhibitor (Brr2-IN-3). Co-immunoprecipitation; ubiquitination assays; mRNA splicing ratio assays; pharmacological inhibition with Brr2-IN-3 Molecular therapy : the journal of the American Society of Gene Therapy Medium 39935176
2025 BRR2/Brr2 functions as an evolutionarily conserved ciR-loop (circRNA-associated R-loop) repressor with dual roles: inhibiting circRNA generation and resolving ciR-loops; loss of Brr2 leads to ciR-loop accumulation, antisense transcription, premature transcription termination, DNA damage, and defects in DNA replication and cell division. Loss-of-function genetics; R-loop detection assays; RNA-seq; DNA damage assays; cell cycle analysis Nature communications Medium 41093835
2013 Dominant-negative mutation in the helicase domain I of human U5-200kD (SNRNP200) expressed in HEK293 cells causes delayed exit from G2/M phase due to splicing defects; shRNA-mediated knockdown of U5-200kD causes S-phase arrest. Dominant-negative expression in ecdysone-inducible system; shRNA knockdown; cell cycle analysis; RT-PCR splicing assays PloS one Medium 23637979

Source papers

Stage 0 corpus · 60 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 RNA unwinding in U4/U6 snRNPs requires ATP hydrolysis and the DEIH-box splicing factor Brr2. Current biology : CB 258 9705931
1998 The human U5-200kD DEXH-box protein unwinds U4/U6 RNA duplices in vitro. Proceedings of the National Academy of Sciences of the United States of America 189 9539711
2009 Autosomal-dominant retinitis pigmentosa caused by a mutation in SNRNP200, a gene required for unwinding of U4/U6 snRNAs. American journal of human genetics 136 19878916
2013 Inhibition of RNA helicase Brr2 by the C-terminal tail of the spliceosomal protein Prp8. Science (New York, N.Y.) 118 23704370
2008 ATP-dependent unwinding of U4/U6 snRNAs by the Brr2 helicase requires the C terminus of Prp8. Nature structural & molecular biology 105 19098916
2009 Structural evidence for consecutive Hel308-like modules in the spliceosomal ATPase Brr2. Nature structural & molecular biology 82 19525970
2012 Structural basis for functional cooperation between tandem helicase cassettes in Brr2-mediated remodeling of the spliceosome. Proceedings of the National Academy of Sciences of the United States of America 80 23045696
2013 Structural basis of Brr2-Prp8 interactions and implications for U5 snRNP biogenesis and the spliceosome active site. Structure (London, England : 1993) 77 23727230
2009 Common design principles in the spliceosomal RNA helicase Brr2 and in the Hel308 DNA helicase. Molecular cell 75 19716790
2012 The Prp8 RNase H-like domain inhibits Brr2-mediated U4/U6 snRNA unwinding by blocking Brr2 loading onto the U4 snRNA. Genes & development 68 23124066
2008 Localization of Prp8, Brr2, Snu114 and U4/U6 proteins in the yeast tri-snRNP by electron microscopy. Nature structural & molecular biology 60 18953335
2015 The large N-terminal region of the Brr2 RNA helicase guides productive spliceosome activation. Genes & development 55 26637280
2011 Next generation sequencing of pooled samples reveals new SNRNP200 mutations associated with retinitis pigmentosa. Human mutation 44 21618346
2016 Functions and regulation of the Brr2 RNA helicase during splicing. Cell cycle (Georgetown, Tex.) 42 27792457
2014 Novel regulatory principles of the spliceosomal Brr2 RNA helicase and links to retinal disease in humans. RNA biology 41 24643059
2017 Discovery of Allosteric Inhibitors Targeting the Spliceosomal RNA Helicase Brr2. Journal of medicinal chemistry 36 28586220
2009 Mutations in ASCC3L1 on 2q11.2 are associated with autosomal dominant retinitis pigmentosa in a Chinese family. Investigative ophthalmology & visual science 35 19710410
2013 Retinitis pigmentosa mutations of SNRNP200 enhance cryptic splice-site recognition. Human mutation 33 24302620
2013 Sad1 counteracts Brr2-mediated dissociation of U4/U6.U5 in tri-snRNP homeostasis. Molecular and cellular biology 31 24190974
2016 Spliceosome SNRNP200 Promotes Viral RNA Sensing and IRF3 Activation of Antiviral Response. PLoS pathogens 28 27454487
2013 Mutations in the small nuclear riboprotein 200 kDa gene (SNRNP200) cause 1.6% of autosomal dominant retinitis pigmentosa. Molecular vision 27 24319334
2005 Multiple genetic and biochemical interactions of Brr2, Prp8, Prp31, Prp1 and Prp4 kinase suggest a function in the control of the activation of spliceosomes in Schizosaccharomyces pombe. Current genetics 27 16133344
2012 A novel missense SNRNP200 mutation associated with autosomal dominant retinitis pigmentosa in a Chinese family. PloS one 26 23029027
2016 Substrate-assisted mechanism of RNP disruption by the spliceosomal Brr2 RNA helicase. Proceedings of the National Academy of Sciences of the United States of America 23 27354531
2016 Interplay of cis- and trans-regulatory mechanisms in the spliceosomal RNA helicase Brr2. Cell cycle (Georgetown, Tex.) 23 27880071
2015 A noncanonical PWI domain in the N-terminal helicase-associated region of the spliceosomal Brr2 protein. Acta crystallographica. Section D, Biological crystallography 23 25849387
2017 Discovery of spiro[indole-3,2'-pyrrolidin]-2(1H)-one based inhibitors targeting Brr2, a core component of the U5 snRNP. Bioorganic & medicinal chemistry 21 28751196
2017 A new role for FBP21 as regulator of Brr2 helicase activity. Nucleic acids research 20 28838205
2015 Brr2 plays a role in spliceosomal activation in addition to U4/U6 unwinding. Nucleic acids research 19 25670679
2023 Systematic evaluation of AML-associated antigens identifies anti-U5 SNRNP200 therapeutic antibodies for the treatment of acute myeloid leukemia. Nature cancer 17 37872381
2016 Retinitis Pigmentosa Mutations in Bad Response to Refrigeration 2 (Brr2) Impair ATPase and Helicase Activity. The Journal of biological chemistry 15 27072132
2017 Variability in clinical phenotypes of PRPF8-linked autosomal dominant retinitis pigmentosa correlates with differential PRPF8/SNRNP200 interactions. Ophthalmic genetics 13 29087248
2013 Cell cycle abnormalities associated with differential perturbations of the human U5 snRNP associated U5-200kD RNA helicase. PloS one 12 23637979
2013 Contribution of SNRNP200 sequence variations to retinitis pigmentosa. Eye (London, England) 12 23887765
2019 Identification of proteins associated with splicing factors Ntr1, Ntr2, Brr2 and Gpl1 in the fission yeast Schizosaccharomyces pombe. Cell cycle (Georgetown, Tex.) 11 31219728
2019 The inactive C-terminal cassette of the dual-cassette RNA helicase BRR2 both stimulates and inhibits the activity of the N-terminal helicase unit. The Journal of biological chemistry 11 31914407
2018 Intrinsically Disordered Protein Ntr2 Modulates the Spliceosomal RNA Helicase Brr2. Biophysical journal 11 29490241
2013 The U5 snRNA internal loop 1 is a platform for Brr2, Snu114 and Prp8 protein binding during U5 snRNP assembly. Journal of cellular biochemistry 11 23857713
2022 A multi-factor trafficking site on the spliceosome remodeling enzyme BRR2 recruits C9ORF78 to regulate alternative splicing. Nature communications 10 35241646
2019 Genotype-Phenotype Analysis of a Novel Recessive and a Recurrent Dominant SNRNP200 Variant Causing Retinitis Pigmentosa. Investigative ophthalmology & visual science 10 31260034
2018 Mutation Analysis of Pre-mRNA Splicing Genes PRPF31, PRPF8, and SNRNP200 in Chinese Families with Autosomal Dominant Retinitis Pigmentosa. Current molecular medicine 10 30360737
2021 SNRNP200 Mutations Cause Autosomal Dominant Retinitis Pigmentosa. Frontiers in medicine 9 33553197
2015 Knocking Down Snrnp200 Initiates Demorphogenesis of Rod Photoreceptors in Zebrafish. Journal of ophthalmology 9 26137319
2012 Spliceosome activation: U4 is the path, stem I is the goal, and Prp8 is the keeper. Let's cheer for the ATPase Brr2! Genes & development 9 23154979
2024 Tracing Allostery in the Spliceosome Ski2-like RNA Helicase Brr2. The journal of physical chemistry letters 8 38517341
2024 Targeting SNRNP200-induced splicing dysregulation offers an immunotherapy opportunity for glycolytic triple-negative breast cancer. Cell discovery 8 39285160
2020 Depletion of SNRNP200 inhibits the osteo-/dentinogenic differentiation and cell proliferation potential of stem cells from the apical papilla. BMC developmental biology 7 33203369
2022 A forward genetic screen in C. elegans identifies conserved residues of spliceosomal proteins PRP8 and SNRNP200/BRR2 with a role in maintaining 5' splice site identity. Nucleic acids research 5 36321655
2018 Specification of Drosophila neuropeptidergic neurons by the splicing component brr2. PLoS genetics 5 30133436
2025 Retinitis pigmentosa-linked mutations impair the snRNA unwinding activity of SNRNP200 and reduce pre-mRNA binding of PRPF8. Cellular and molecular life sciences : CMLS 4 40045025
2021 Generation of two induced pluripotent stem cell lines from a patient with recessive inherited retinal disease caused by compound heterozygous mutations in SNRNP200. Stem cell research 4 33429167
2025 Dual roles of DEAD-box RNA helicase Brr2 in genome stability regulation. Nature communications 3 41093835
2021 Long-range allostery mediates cooperative adenine nucleotide binding by the Ski2-like RNA helicase Brr2. The Journal of biological chemistry 3 34048711
2025 Y4 RNA fragment alleviates myocardial injury in heart transplantation via SNRNP200 to enhance IL-10 mRNA splicing. Molecular therapy : the journal of the American Society of Gene Therapy 2 39935176
2018 FBP21's C-Terminal Domain Remains Dynamic When Wrapped around the c-Sec63 Unit of Brr2 Helicase. Biophysical journal 2 30558886
2017 Correction: Spliceosome SNRNP200 Promotes Viral RNA Sensing and IRF3 Activation of Antiviral Response. PLoS pathogens 2 28118396
2013 [Targeted sequencing identifies a hotspot mutation SNRNP200 p.S1087L correlates with novel phenotypes in retinitis pigmentosa]. [Zhonghua yan ke za zhi] Chinese journal of ophthalmology 1 24499697
2025 Likely Pathogenic/Pathogenic Variants in the Spliceosome Complex Genes SNRNP200, SF3B1, SF3B2, and SF3B4 Implicated in Nonsyndromic Orofacial Cleft. Human mutation 0 41427026
2023 Conformation-dependent ligand hot spots in the spliceosomal RNA helicase BRR2. Acta crystallographica. Section D, Structural biology 0 36974964
2021 Characterization of the Brr2 RNA Helicase and Its Regulation by Other Spliceosomal Proteins Using Gel-Based U4/U6 Di-snRNA Binding and Unwinding Assays. Methods in molecular biology (Clifton, N.J.) 0 33201471