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Showing SNRNP200 — BRR2 is a alias.

SNRNP200

U5 small nuclear ribonucleoprotein 200 kDa helicase · UniProt O75643

Length
2136 aa
Mass
244.5 kDa
Annotated
2026-06-10
60 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SNRNP200 (human Brr2/U5-200kD) is the ATP-dependent RNA helicase that catalyzes unwinding of the U4/U6 snRNA duplex to drive catalytic activation of the spliceosome (PMID:9705931, PMID:9539711). The enzyme is built from two tandem Ski2-like/Hel308-related helicase cassettes, each comprising RecA-like domains plus a Sec63 unit, but only the N-terminal cassette is catalytically active; the structurally similar C-terminal cassette is enzymatically inactive yet binds nucleotide and strongly stimulates the active cassette, and the two communicate allosterically across an intercassette interface ~70 Å apart (PMID:19525970, PMID:19716790, PMID:23045696, PMID:34048711). Mechanistically, Brr2 loads on a single-stranded region of U4, translocates along the U4 strand, and processively unwinds a limited portion of the duplex, with final separation completed when U6 adopts an alternative conformation, releasing an intact Prp31–Snu13–U4 particle, free Prp3, and free U6 (PMID:27354531). Its activity is held in check by multiple layers of regulation: an N-terminal region that autoinhibits by competing with substrate and clamping the cassettes (PMID:26637280, PMID:27880071), and the surrounding Prp8 protein, whose RNase H domain, C-terminal tail, and Jab1/MPN domain variously block or stimulate the helicase—the C-terminal tail inserting directly into Brr2's RNA-binding tunnel while the Jab1/MPN domain binds the active cassette and activates unwinding (PMID:23124066, PMID:23704370, PMID:23727230, PMID:31914407). Relative reorientation of the two cassettes itself toggles activity, as shown by engineered disulfide bridges that either enhance or inhibit unwinding (PMID:31914407). Accessory factors FBP21, Ntr2, and C9ORF78 wrap the C-terminal cassette to tune activity—C9ORF78 governing BRR2-dependent alternative splice-site selection—while Sad1 protects tri-snRNP integrity against premature Brr2-driven dissociation (PMID:24190974, PMID:28838205, PMID:29490241, PMID:35241646). Beyond its catalytic core, the N-terminal region maintains 5′ splice-site identity and retention of U5/U6 during activation (PMID:25670679, PMID:36321655). Retinitis pigmentosa type 33 is caused by SNRNP200 ratchet-helix mutations (S1087L, R1090L) that impair RNA binding, translocation, ATPase activity, and U4/U6 unwinding without disrupting snRNP assembly, instead promoting cryptic/aberrant splice-site usage and slowed splicing (PMID:19878916, PMID:24302620, PMID:27072132, PMID:40045025).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1998 High

    Established the foundational identity of Brr2/SNRNP200 as the ATP-dependent helicase responsible for unwinding the U4/U6 duplex, the key RNA rearrangement of spliceosome activation.

    Evidence Immunopurified native yeast snRNP complex with ATP-driven unwinding and helicase-domain mutant analysis; parallel purification of the human U5-200kD protein with in vitro unwinding activity

    PMID:9539711 PMID:9705931

    Open questions at the time
    • Did not resolve the domain architecture executing unwinding
    • Directionality and processivity of translocation unknown
    • Regulation within the tri-snRNP not addressed
  2. 2008 Medium

    Defined the spatial organization of Brr2 within the tri-snRNP and revealed Prp8 as a paradoxical regulator that stimulates unwinding while inhibiting ATPase activity, linking Prp8 RP alleles to defective activation.

    Evidence EM projection structure of tagged yeast tri-snRNP; in vitro unwinding and ATPase assays with Prp8 C-terminal fragments and RP-linked alleles

    PMID:18953335 PMID:19098916

    Open questions at the time
    • Atomic basis of Prp8 stimulation/inhibition not resolved
    • How dynamic domain rearrangements couple to catalysis unclear
  3. 2009 High

    Crystal structures revealed Brr2's two tandem Hel308-like cassettes and showed the RecA-like plus Sec63 units form a processive, unidirectional unwinding engine that physically engages Prp8 and Snu114.

    Evidence Crystal structures of Brr2 Sec63 units with rational mutagenesis, splicing and U4/U6 unwinding assays, and interaction validation

    PMID:19525970 PMID:19716790

    Open questions at the time
    • Functional asymmetry between the two cassettes not yet established
    • Full-length regulatory architecture unresolved
  4. 2009 Medium

    Connected SNRNP200 to human disease by showing RP33 ratchet-helix mutations selectively impair U4/U6 unwinding while leaving snRNP assembly intact, pinpointing the catalytic defect underlying retinitis pigmentosa.

    Evidence Yeast genetic complementation and U4/U6 unwinding assays with mutant proteins (analogous N1104L/R1107L)

    PMID:19878916

    Open questions at the time
    • Consequence for splice-site fidelity not yet shown
    • Tissue-specific (retinal) vulnerability unexplained
  5. 2012 High

    Resolved the two-cassette division of labor and a Prp8 RNase H-mediated negative-regulatory mechanism, showing the active N-terminal cassette threads ssRNA while the inactive C-terminal cassette acts as an allosteric stimulator.

    Evidence Crystal structures and isolated-cassette ATPase/helicase assays; cross-linking/MS mapping of Prp8 RH–U4 contacts with unwinding-inhibition assays

    PMID:23045696 PMID:23124066

    Open questions at the time
    • How autoinhibition and Prp8 control are integrated unresolved
    • Timing of inhibition release during activation unknown
  6. 2013 High

    Defined three distinct Prp8 modules (C-terminal tail, Jab1/MPN, RNase H) as direct, mechanistically separable Brr2 regulators—the tail plugging the RNA tunnel and Jab1/MPN binding the active cassette to stimulate it—and identified Sad1 as a guardian of tri-snRNP integrity.

    Evidence Crystal structures of Brr2–Prp8 tail and Brr2–Jab1/MPN complexes with ATPase/unwinding assays; in vitro tri-snRNP dissociation assays plus yeast genetics for Sad1; U5 IL1 mutagenesis; cell-cycle perturbation

    PMID:23637979 PMID:23704370 PMID:23727230 PMID:23857713 PMID:24190974

    Open questions at the time
    • How the multiple Prp8 contacts are temporally switched during the catalytic cycle unclear
    • Sad1 mechanism characterized only in yeast
  7. 2013 Medium

    Linked the RP33 helicase defect to splicing fidelity by showing the mutations enhance cryptic splice-site usage and that BRR2 is required for correct 5′ splice-site selection in human cells.

    Evidence BAC-recombineered stable mutant human cell lines, RNAi knockdown, and splicing rescue assays

    PMID:24302620

    Open questions at the time
    • Mechanistic basis for fidelity role not resolved
    • Single-lab cell-line study
  8. 2015 High

    Identified the N-terminal region as an autoinhibitory and assembly module that clamps the cassettes, supports U5/U6 retention during activation, and engages spliceosomal partners such as SPF27 via a PWI-like domain.

    Evidence Full-length Brr2–Jab1/MPN crystal structure with truncation series and in vivo splicing assays; PWI-like domain structure with yeast two-hybrid interaction screen; truncation phenotypes in spliceosomal complexes

    PMID:25670679 PMID:25849387 PMID:26637280

    Open questions at the time
    • How N-terminal autoinhibition is relieved in vivo unknown
    • Physiological relevance of SPF27 interaction unresolved
  9. 2016 High

    Reconstituted the complete unwinding reaction, showing Brr2 translocates on U4, unwinds only a limited duplex region without displacing proteins, with completion requiring a U6 conformational switch and inhibition by assembled U4/U6 proteins that Prp8 Jab1/MPN relieves.

    Evidence Fully reconstituted Brr2-mediated di-snRNP disruption system with purified components and mutant RNA substrates; crystal structures of Brr2–Jab1 from two species; biochemical dissection of RP mutants and Jab1 stimulation

    PMID:27072132 PMID:27354531 PMID:27880071

    Open questions at the time
    • Coordination with downstream activation steps in the intact spliceosome not addressed
    • RP mutant defects shown in vitro only
  10. 2016 Medium

    Revealed a noncanonical, splicing-independent function in which SNRNP200 relocalizes to cytoplasmic TBK1 structures, binds viral RNA via its Sec63-1 domain, and promotes IRF3-mediated antiviral signaling—disrupted by the RP33 S1087L mutant.

    Evidence Immunofluorescence, Co-IP with TBK1, RNA binding, and knockdown rescue including RP33 patient cells infected with Sendai virus

    PMID:27454487

    Open questions at the time
    • Mechanism of nuclear-to-cytoplasmic relocalization unknown
    • Single-lab finding outside canonical splicing role
  11. 2017 Medium

    Expanded the regulatory network by establishing FBP21 as an allosteric inhibitor that both binds the C-terminal Sec63 unit and sequesters U4/U6 substrate.

    Evidence Yeast two-hybrid, SPR/biophysical binding, and helicase activity assays

    PMID:28838205

    Open questions at the time
    • In vivo significance of FBP21 inhibition not established
    • Single-lab study
  12. 2018 Medium

    Showed the disassembly factor Ntr2 downregulates Brr2 by binding the C-terminal cassette and lowering the productively RNA-bound helicase fraction, defining another C-terminal-cassette-targeted regulator.

    Evidence Multiple biophysical methods (NMR, CD, SPR, SEC) plus RNA binding and unwinding assays

    PMID:29490241

    Open questions at the time
    • Cellular context of Ntr2 inhibition unresolved
    • Characterized in yeast only
  13. 2019 High

    Demonstrated that the relative orientation of the two helicase cassettes is itself a control switch for unwinding activity, providing a structural mechanism for activation/inhibition.

    Evidence 2.4 Å human BRR2–Prp8 domain crystal structure and engineered disulfide bridges locking cassettes in two orientations with opposite functional effects

    PMID:31914407

    Open questions at the time
    • How natural effectors drive these reorientations in vivo unclear
    • Coupling to ATP cycle not detailed
  14. 2021 Medium

    Quantified the allosteric basis of cassette cooperation, showing the inactive C-terminal cassette is a high-affinity ADP/ATP sensor that transmits nucleotide-binding signals ~70 Å to the active cassette across the intercassette interface.

    Evidence Biophysical nucleotide-binding assays, intercassette-interface mutagenesis, and molecular dynamics simulations

    PMID:34048711

    Open questions at the time
    • Physiological trigger for C-terminal nucleotide exchange unknown
    • Single-lab biophysical study
  15. 2022 High

    Established C9ORF78 as a structural regulator that competes with FBP21 on the C-terminal cassette and controls BRR2-dependent alternative splicing, and identified an N-terminal residue maintaining 5′ splice-site identity.

    Evidence Cryo-EM of BRR2–C9ORF78/FBP21, AP-MS, RNA crosslinking, and RNA-seq after knockdown; C. elegans forward genetic suppressor screen with mRNA-seq and structural mapping

    PMID:35241646 PMID:36321655

    Open questions at the time
    • Full repertoire of C9ORF78-regulated transcripts not defined
    • Mechanism linking N-terminus to splice-site selection unresolved
  16. 2024 Medium

    Linked SNRNP200 to metabolic regulation by showing glucose-induced K1610 acetylation stabilizes the protein and promotes splicing of glycolytic enzyme transcripts in breast cancer.

    Evidence Multi-omics, acetylation-site mapping, antisense oligonucleotide depletion, and metabolic assays

    PMID:39285160

    Open questions at the time
    • Acetyltransferase/deacetylase responsible not identified
    • Generality beyond TNBC unknown
  17. 2025 Medium

    Refined the disease mechanism by showing RP33 mutations broaden snRNA binding upstream of stem I, impair unwinding and translocation, and indirectly reduce PRPF8 pre-mRNA binding to slow splicing; and identified RNA-mediated stabilization of SNRNP200 affecting cytokine splicing.

    Evidence iCLIP, FRAP, helicase assays and transcriptomics in human cells for RP mutants; Y4 RNA fragment binding, ubiquitination, and IL-10 splicing assays with pharmacological inhibition

    PMID:39935176 PMID:40045025

    Open questions at the time
    • Causal chain from altered binding to retinal degeneration incomplete
    • Endogenous ubiquitin machinery regulating SNRNP200 not defined
  18. 2025 Medium

    Revealed a non-spliceosomal genome-protective role in which Brr2 represses circRNA back-splicing and resolves circular RNA–DNA hybrids (ciR-loops) to prevent DNA damage and replication defects.

    Evidence Loss-of-function genetics, ciR-loop detection, transcriptomics, DNA damage assays, and conservation analysis

    PMID:41093835

    Open questions at the time
    • Whether ciR-loop resolution uses the canonical helicase activity unclear
    • Relationship to the splicing function not delineated
    • Single study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse layers of Brr2 regulation (autoinhibition, Prp8 modules, accessory factors, cassette reorientation, PTMs) are temporally orchestrated within the assembling spliceosome in vivo, and why catalytic defects manifest as retina-specific disease, remain open.
  • No integrated in vivo model of regulatory switching during activation
  • Tissue specificity of RP33 pathology unexplained
  • Mechanistic basis of non-canonical antiviral, metabolic, and ciR-loop functions incompletely resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 4 GO:0140657 ATP-dependent activity 4 GO:0003723 RNA binding 3 GO:0016787 hydrolase activity 2
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-8953854 Metabolism of RNA 3
Partners
AAR2C9ORF78FBP21NTR2PRPF8SAD1SNU114TBK1
Complex memberships
U4/U6•U5 tri-snRNPU5 snRNPspliceosome

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Brr2 (yeast ortholog of SNRNP200) was immunopurified in a native complex containing U1, U2, U5, and duplex U4/U6 snRNPs. Addition of hydrolyzable ATP to this complex disrupts U4/U6 base-pairing and releases free U4 and U6 snRNPs; a mutation in the helicase-like domain (brr2-1) prevents these RNA rearrangements, establishing Brr2 as the ATP-dependent helicase responsible for U4/U6 unwinding. Immunopurification of native snRNP complex, ATP hydrolysis assay, helicase-domain mutant analysis Current biology : CB High 9705931
1998 Purified human U5-200kD (SNRNP200) protein, isolated by glycerol gradient centrifugation and ion exchange chromatography, harbors the ATP-dependent RNA unwinding activity capable of disrupting U4/U6 RNA duplexes in vitro; U5 snRNPs depleted of U5-100kD but retaining U5-200kD retained this activity, localizing the helicase function to U5-200kD. Biochemical fractionation, depletion of snRNP subsets under high salt, in vitro RNA unwinding assay with purified protein Proceedings of the National Academy of Sciences of the United States of America High 9539711
2008 The C-terminal region of Prp8 (Prp8-CTR) activates Brr2-dependent dissociation of U4/U6 snRNAs in vitro, while paradoxically inhibiting the Brr2 U4/U6-dependent ATPase activity; Prp8 fragments carrying retinitis pigmentosa-linked alleles failed to stimulate U4/U6 unwinding activity. In vitro U4/U6 unwinding assay, ATPase activity assay, Prp8 fragment biochemistry Nature structural & molecular biology High 19098916
2008 By electron microscopy of tagged yeast tri-snRNP, Brr2 was localized to a distinct 'head' domain of the tri-snRNP, separate from a U4/U6 snRNP 'arm' domain, while Prp8 and GTPase Snu114 are positioned centrally; the head and arm domains adopt variable relative positions, suggesting dynamic structural rearrangements during spliceosome activation. EM projection structure of tri-snRNP with genetically tagged proteins Nature structural & molecular biology Medium 18953335
2009 Crystal structure of the second Sec63 domain of Brr2 revealed unexpected structural similarity to domains 4 and 5 of DNA helicase Hel308, leading to a structural model of two consecutive Hel308-like modules (Hel308-I and Hel308-II) in Brr2. Mutagenesis validated helicase mechanism. The C-terminal helicase cassette (Hel308-II) interacts with Prp8 and Snu114 both in vitro and in vivo. Crystal structure determination, rational mutagenesis, splicing and U4/U6 unwinding assays, in vitro and in vivo interaction assays Nature structural & molecular biology High 19525970
2009 Crystal structures of the C-terminal Sec63 unit of yeast Brr2 revealed three domains, two of which resemble functional modules of Hel308 DNA helicase. Rational mutagenesis combined with splicing and U4/U6 di-snRNA unwinding assays demonstrated that the RecA-like domains and Sec63 unit form a functional entity for unidirectional and processive RNA duplex unwinding. Crystal structure, rational mutagenesis, splicing assays, U4/U6 di-snRNA unwinding assays Molecular cell High 19716790
2009 RP33-linked mutations p.S1087L and p.R1090L in the 'ratchet' helix of the first Sec63 domain of SNRNP200 (hBrr2) cause marked defects in U4/U6 unwinding in budding yeast (analogous mutations N1104L and R1107L in Brr2p), without affecting U4/U6-U5 snRNP assembly. Yeast genetic complementation, U4/U6 unwinding assays with mutant proteins American journal of human genetics Medium 19878916
2012 The RNase H (RH) domain of yeast Prp8 binds U4/U6 snRNA at single-stranded regions preceding U4/U6 stem I. The same single-stranded U4 region is recognized by Brr2 for translocation and unwinding of stem I first. The RH domain of Prp8 blocks Brr2's interaction with U4 snRNA, thereby inhibiting U4/U6 unwinding—a negative regulatory mechanism preventing premature activation. Cross-linking coupled with mass spectrometry, RNA binding assays, U4/U6 unwinding inhibition assays Genes & development High 23124066
2012 In human Brr2, the two ring-like helicase cassettes intimately interact and functionally cooperate: only the N-terminal cassette harbors ATPase and helicase activities in isolation, but the C-terminal cassette binds ATP and strongly stimulates the N-terminal helicase. Single-stranded RNA is threaded through the N-terminal cassette. RP-linked Brr2 mutations interfere with the enzyme's function and cassette cross-talk. Crystal structures, mutational analysis, ATPase and helicase assays with isolated cassettes and full-length protein Proceedings of the National Academy of Sciences of the United States of America High 23045696
2013 Crystal structure and biochemical analyses showed that the C-terminal tail of Prp8 inserts into Brr2's RNA-binding tunnel, directly competing with RNA substrate binding and thereby inhibiting Brr2's RNA-binding, ATPase, and U4/U6 unwinding activities. RP-linked Prp8 mutations in the C-terminal tail impair this inhibitory mechanism (inefficient Brr2 repression is the only phenotype). Crystal structure of Brr2-Prp8 C-terminal tail complex, ATPase assay, U4/U6 unwinding assay, mutagenesis Science (New York, N.Y.) High 23704370
2013 Crystal structure of yeast Brr2 in complex with the Jab1/MPN domain of Prp8 showed that the Jab1/MPN domain binds exclusively to the N-terminal helicase cassette of Brr2 and stimulates Brr2 activity. RP-causing residues of Prp8 map to or near the Brr2 interface. Aar2 and Brr2 are mutually exclusive in U5 snRNP assembly: Brr2 replaces Aar2 after nuclear import. Crystal structure, mutagenesis, U5 snRNP assembly analysis Structure (London, England : 1993) High 23727230
2013 Yeast Sad1 counteracts Brr2-mediated ATP-dependent dissociation of the U4/U6.U5 tri-snRNP into U5 and U4/U6, thereby maintaining tri-snRNP integrity. In the absence of Sad1, Brr2-driven ATP hydrolysis dissociates tri-snRNP and prevents its binding to the spliceosome. In vitro tri-snRNP dissociation/reassociation assays, ATP hydrolysis assays, genetic analysis in yeast Molecular and cellular biology Medium 24190974
2013 RP-linked mutations in SNRNP200 (S1087L and R1090L) do not compromise snRNP assembly or spliceosome incorporation but enhance usage of cryptic splice sites; depletion of BRR2 inhibited correct splice-site usage and this was rescued by wild-type but not RP mutant BRR2, implicating BRR2 in 5'-splice-site fidelity. BAC recombineering to introduce stable mutations in human cells, RNAi knockdown, splicing assays Human mutation Medium 24302620
2013 U5 snRNA internal loop 1 (IL1) serves as a platform for Brr2, Prp8, and Snu114 binding during U5 snRNP assembly in yeast; mutations in the 3' side of U5 IL1 caused the greatest reduction in association of all three proteins, and synthetic lethal interactions between brr2 and U5 IL1 alleles were identified. Site-directed mutagenesis of U5 snRNA, co-immunoprecipitation, genetic synthetic lethality screen Journal of cellular biochemistry Medium 23857713
2015 Crystal structure of full-length Brr2 in complex with the Prp8 Jab1/MPN domain revealed that the N-terminal region (~500 residues) of Brr2 encompasses two folded domains and adjacent linear elements that clamp and interconnect the helicase cassettes. N-terminal truncations caused yeast growth/splicing defects, reduced tri-snRNP association, and increased ATP-dependent tri-snRNP disruption. The N-terminal region autoinhibits Brr2 via substrate competition and conformational clamping. Crystal structure of full-length Brr2, cross-linking/mass spectrometry, stepwise N-terminal truncation series with in vivo splicing assays, RNA-binding, ATPase, and helicase assays Genes & development High 26637280
2015 Crystal structure of the N-terminal helicase-associated region of Brr2 (Chaetomium thermophilum) revealed a noncanonical PWI-like domain that lacks significant nucleic acid-binding activity. Instead, yeast two-hybrid screening showed that the N-terminal region of human Brr2 interacts with several spliceosomal proteins, including SPF27 (a Prp19 complex protein), in a manner dependent on the PWI-like domain. Crystal structure, CD spectroscopy, band-shift assays, yeast two-hybrid screen Acta crystallographica. Section D, Biological crystallography Medium 25849387
2015 Deletion of the N-terminal 120 residues of yeast Brr2 does not significantly impair helicase activity or tri-snRNP assembly, but severely impairs spliceosomal activation; specifically, the N-terminal truncation causes dramatic reduction of U5 and U6 snRNAs and accumulation of U1 snRNA in the Bact complex, indicating a role in retaining U5/U6 snRNPs during/after spliceosomal activation. Yeast genetics (truncation mutants), spliceosome assembly assays, snRNA analysis in spliceosomal complexes Nucleic acids research Medium 25670679
2016 Brr2 translocates along the U4 snRNA strand, actively unwinds only a limited region of U4/U6 duplex, and does not actively displace RNA-bound proteins. Using a recombinant Brr2-mediated U4/U6 di-snRNP disruption system, sequential addition of U4/U6 proteins (Snu13, Prp31, Prp3) progressively inhibited Brr2-mediated unwinding, which was largely restored by the Prp8 Jab1/MPN domain. After unwinding, Brr2 segregates the complex into an intact Prp31-Snu13-U4 snRNA particle plus free Prp3 and free U6 snRNA; final unwinding completion is achieved by U6 adopting an alternative conformation. Reconstituted in vitro Brr2-mediated di-snRNP disruption system with purified components, RNA unwinding assays, mutant U4/U6 di-snRNA analysis Proceedings of the National Academy of Sciences of the United States of America High 27354531
2016 Crystal structures of Saccharomyces cerevisiae and Chaetomium thermophilum Brr2-Jab1 complexes showed that Jab1-based inhibition of Brr2 is evolutionarily conserved but implemented via organism-specific molecular contacts. Brr2 N-terminal region auto-inhibition and Jab1-mediated inhibition act in concert and mutually reinforce each other: the N-terminal region specifically interferes with accommodation of double-stranded RNA, while the Jab1 C-terminal tail blocks single-stranded RNA accommodation. N-terminal auto-inhibition requires the inactive C-terminal helicase cassette. Crystal structures of two Brr2-Jab1 complexes from different species, systematic RNA binding and unwinding studies Cell cycle (Georgetown, Tex.) High 27880071
2016 RP-linked mutations in Brr2 (S1087L, R1090L) impair RNA binding, helicase activity, and ATPase activity in a gradient of severity; the Jab1/MPN domain of Prp8 increases Brr2's ability to bind U4/U6 duplex and stimulates ATPase and RNA unwinding, but does not differentially rescue RP mutants versus wild-type. RP mutations impair translocation through RNA helices. In vitro ATPase assays, helicase assays, RNA binding assays with purified recombinant Brr2 truncation and RP mutants, Prp8 Jab1 domain stimulation assays The Journal of biological chemistry Medium 27072132
2016 SNRNP200 promotes viral RNA sensing and IRF3-mediated antiviral response. Upon viral infection, SNRNP200 relocalizes from the nucleus into TBK1-containing cytoplasmic structures. SNRNP200's N-terminal Sec63 domain (Sec63-1) binds viral RNA and interacts with TBK1. The RP33-associated S1087L mutant fails to relocalize and cannot rescue antiviral response in knockdown cells. Immunofluorescence localization, co-immunoprecipitation with TBK1, RNA binding assays, knockdown rescue experiments, peripheral blood cells from RP33 patients infected with Sendai virus PLoS pathogens Medium 27454487
2017 FBP21 binds to the C-terminal Sec63 unit of Brr2 via an intrinsically disordered region, and this interaction allosterically inhibits Brr2 helicase activity. FBP21 also directly binds U4/U6 di-snRNA, reducing the pool of unwound substrate. Yeast two-hybrid screen, biochemical binding assays, biophysical analyses (SPR), RNA helicase activity assays Nucleic acids research Medium 28838205
2017 Two classes of small-molecule Brr2 inhibitors were identified: one binding an allosteric site between the C-terminal and N-terminal helicase cassettes, and a second binding an RNA-binding site inside the N-terminal cassette. Cocrystal structures of both inhibitors with Brr2 confirmed binding modes; the allosteric inhibitor shows greater Brr2 selectivity. HTS RNA-dependent ATPase assay, cocrystal structures, SAR optimization, helicase inhibition assays, selectivity profiling Journal of medicinal chemistry High 28586220
2018 Yeast spliceosomal disassembly factor Ntr2 is largely intrinsically disordered and uses its N-terminal region to bind the C-terminal helicase unit of Brr2; Ntr2 downregulates Brr2 helicase activity in vitro by modulating the fraction of helicase molecules productively bound to the RNA substrate. CD spectroscopy, dynamic light scattering, NMR spectroscopy, peptide SPOT analyses, analytical SEC, SPR, RNA binding and unwinding assays Biophysical journal Medium 29490241
2019 Crystal structure of human BRR2 in complex with an activating Prp8 domain at 2.4 Å resolution showed that the N- and C-terminal cassettes adopt vastly different relative orientations compared to BRR2 alone. Engineered disulfide bridges locking cassettes in two different relative orientations had opposite effects on RNA-unwinding activity (one configuration enhancing, the other inhibiting), demonstrating that relative cassette positioning controls BRR2 activity. Crystal structure (2.4 Å), engineered disulfide bridge cross-linking, RNA-stimulated ATPase assays, RNA unwinding assays The Journal of biological chemistry High 31914407
2021 Brr2 exhibits high specificity for adenine nucleotides; the inactive C-terminal cassette binds ADP tighter than ATP (>100-fold higher affinity than the active N-terminal cassette). Mutations at the intercassette interface reduce nucleotide affinity for both cassettes; abrogation of nucleotide binding at the C-terminal cassette reduces binding at the N-terminal cassette ~70 Å away, revealing long-range allosteric communication mediated predominantly across the intercassette interface. Biophysical nucleotide binding assays, mutagenesis of intercassette surfaces, molecular dynamics simulations The Journal of biological chemistry Medium 34048711
2022 C9ORF78 tightly interacts with BRR2 in vitro. Cryo-EM structures revealed that C9ORF78 and FBP21 wrap around the C-terminal helicase cassette of BRR2 in a mutually exclusive manner. Knockdown of C9ORF78 leads to alternative NAGNAG 3'-splice site usage and exon skipping dependent on BRR2, establishing C9ORF78 as a regulator of BRR2-dependent alternative splicing. Cryo-EM structures, affinity purification/mass spectrometry, RNA UV-crosslinking, in vitro binding assays, RNA-seq after knockdown Nature communications High 35241646
2022 A forward genetic screen in C. elegans identified a suppressor allele at the unstructured N-terminus of SNRNP200 (N18K) that suppresses a 5' splice-site mutation defect, revealing a novel role for the N-terminal region of SNRNP200 in maintaining 5' splice-site identity during spliceosome assembly. Forward genetic screen in C. elegans, mRNA-seq of suppressor strains, double mutant epistasis analysis, mapping onto cryo-EM spliceosome structures Nucleic acids research Medium 36321655
2024 Glucose induces acetylation of SNRNP200 at K1610, preventing its proteasomal degradation. Stabilized SNRNP200 then facilitates splicing of key metabolic enzyme-encoding genes (GAPDH, ALDOA, and GSS), leading to increased lactic acid and glutathione production in glycolytic triple-negative breast cancer. Multi-omics analysis (proteomics/transcriptomics), acetylation site identification, antisense oligonucleotide depletion, metabolic assays Cell discovery Medium 39285160
2025 RP-linked mutations S1087L and R1090L in SNRNP200 change its interaction profile with U4 and U6 snRNAs (broader binding upstream of U4/U6 stem I), indicating impaired snRNA unwinding activity, confirmed by FRAP measurements and helicase activity assays. These mutations also indirectly reduce pre-mRNA binding of PRPF8, resulting in slower intron splicing. iCLIP in HeLa and RPE cells, FRAP measurements, helicase activity assays, transcriptomics in RPE cells Cellular and molecular life sciences : CMLS Medium 40045025
2025 Y4 RNA fragment (YF1) binds SNRNP200 and reduces its ubiquitination, thereby stabilizing SNRNP200 protein and enhancing IL-10 pre-mRNA splicing in macrophages; this effect is reversed by a specific SNRNP200 inhibitor (Brr2-IN-3). Biochemical binding assays, ubiquitination assays, mRNA splicing assays (IL-10 mRNA/pre-IL-10 ratio), pharmacological inhibition Molecular therapy : the journal of the American Society of Gene Therapy Medium 39935176
2025 Brr2 acts as a ciR-loop repressor with dual roles: (1) inhibiting circRNA generation (back-splicing), and (2) resolving harmful ciR-loops (circular RNA–DNA hybrids). Loss of Brr2 causes accumulation of ciR-loops, antisense transcription, premature transcription termination, DNA damage, and defects in DNA replication and cell division. Loss-of-function genetic analysis, ciR-loop detection assays, transcriptomics, DNA damage assays, evolutionary conservation analysis Nature communications Medium 41093835
2013 Differential perturbation of U5-200kD (SNRNP200) in human cells reveals distinct cell cycle phenotypes: expression of a dominant-negative helicase domain I mutant causes G2/M phase delay, while RNAi knockdown of endogenous U5-200kD causes S-phase arrest, both associated with splicing defects. Dominant-negative mutant expression (ecdysone-inducible system), RNAi knockdown, cell cycle analysis, splicing analysis in HEK293 cells PloS one Medium 23637979
2030 AML cells display surface localization of U5 snRNP200 linked to surface expression of FcγRIIIA (CD32A). Cell membrane localization was identified by high-density immunophenotyping and proteogenomics. High-density immunophenotyping, proteogenomics Nature cancer Low 37872381

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 138 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.) 43 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 37 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 32 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
2012 A novel missense SNRNP200 mutation associated with autosomal dominant retinitis pigmentosa in a Chinese family. PloS one 27 23029027
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
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 13 23637979
2019 Identification of proteins associated with splicing factors Ntr1, Ntr2, Brr2 and Gpl1 in the fission yeast Schizosaccharomyces pombe. Cell cycle (Georgetown, Tex.) 12 31219728
2013 Contribution of SNRNP200 sequence variations to retinitis pigmentosa. Eye (London, England) 12 23887765
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
2024 Targeting SNRNP200-induced splicing dysregulation offers an immunotherapy opportunity for glycolytic triple-negative breast cancer. Cell discovery 10 39285160
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
2025 Dual roles of DEAD-box RNA helicase Brr2 in genome stability regulation. Nature communications 7 41093835
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
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

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