Molecular architecture of the human U4/U6.U5 tri-snRNP

Agafonov, Dmitry E.; Kastner, Berthold; Dybkov, Olexandr; Hofele, Romina V.; Liu, Wen-Ti; Urlaub, Henning; Lührmann, Reinhard; Stark, Holger

doi:10.1126/science.aad2085

Cited by 180 publications

(245 citation statements)

References 52 publications

(64 reference statements)

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“…In a recent cryo-EM structure of a human U4/U6 U5 trisnRNP, 14 Brr2 was found in an auto-inhibited conformation with the NTR folded back onto the helicase cassettes, very similar to the situation in isolated Brr2-Jab1 complexes 55,56 ( Fig. 4A,B).…”

Section: Brr2 Regulation In the Tri-snrnpsupporting

confidence: 53%

“…On the other hand, isolated Brr2 is a comparatively weak helicase, 25,40,41 and its U4/U6 di-snRNA substrate is stabilized by extensive base pairing and bound proteins, [12][13][14]29,42,43 suggesting that the helicase may also depend on specific activation to efficiently unwind the U4/U6 duplex at the right time.…”

Section: Brr2 Requires Tight Regulationmentioning

confidence: 99%

“…Subsequently, the pre-formed U4/U6 U5 tri-snRNP loosely associates with the spliceosome, giving rise to the catalytically inactive pre-B complex. 8 Within the tri-snRNP, the U4 and U6 snRNAs are extensively base-paired via 2 regions (stems I and II) [9][10][11][12][13][14] and decorated by several proteins. [12][13][14] Association of the U4/U6 di-snRNP with the U5 snRNP is mainly accomplished by protein-protein interactions.…”

Section: Introductionmentioning

confidence: 99%

“…8 Within the tri-snRNP, the U4 and U6 snRNAs are extensively base-paired via 2 regions (stems I and II) [9][10][11][12][13][14] and decorated by several proteins. [12][13][14] Association of the U4/U6 di-snRNP with the U5 snRNP is mainly accomplished by protein-protein interactions. [12][13][14][15] After pre-B complex formation, the U1 snRNP is released and the tri-snRNP is stably integrated to produce the pre-catalytic B complex, followed by displacement of U4 snRNAs and associated proteins, which leads to the activated spliceosome (B act ).…”

Section: Introductionmentioning

confidence: 99%

“…[12][13][14] Association of the U4/U6 di-snRNP with the U5 snRNP is mainly accomplished by protein-protein interactions. [12][13][14][15] After pre-B complex formation, the U1 snRNP is released and the tri-snRNP is stably integrated to produce the pre-catalytic B complex, followed by displacement of U4 snRNAs and associated proteins, which leads to the activated spliceosome (B act ). 16 Further remodeling of B act gives rise to the catalytically activated spliceosome (B Ã ).…”

Section: Introductionmentioning

confidence: 99%

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Functions and regulation of the Brr2 RNA helicase during splicing

2016

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Pre-mRNA splicing entails the stepwise assembly of an inactive spliceosome, its catalytic activation, splicing catalysis and spliceosome disassembly. Transitions in this reaction cycle are accompanied by compositional and conformational rearrangements of the underlying RNA-protein interaction networks, which are driven and controlled by 8 conserved superfamily 2 RNA helicases. The Ski2-like helicase, Brr2, provides the key remodeling activity during spliceosome activation and is additionally implicated in the catalytic and disassembly phases of splicing, indicating that Brr2 needs to be tightly regulated during splicing. Recent structural and functional analyses have begun to unravel how Brr2 regulation is established via multiple layers of intra-and inter-molecular mechanisms. Brr2 has an unusual structure, including a long N-terminal region and a catalytically inactive C-terminal helicase cassette, which can auto-inhibit and auto-activate the enzyme, respectively. Both elements are essential, also serve as protein-protein interaction devices and the N-terminal region is required for stable Brr2 association with the tri-snRNP, tri-snRNP stability and retention of U5 and U6 snRNAs during spliceosome activation in vivo. Furthermore, a C-terminal region of the Prp8 protein, comprising consecutive RNase H-like and Jab1/MPN-like domains, can both up-and downregulate Brr2 activity. Biochemical studies revealed an intricate cross-talk among the various cis-and transregulatory mechanisms. Comparison of isolated Brr2 to electron cryo-microscopic structures of yeast and human U4/U6 U5 tri-snRNPs and spliceosomes indicates how some of the regulatory elements exert their functions during splicing. The various modulatory mechanisms acting on Brr2 might be exploited to enhance splicing fidelity and to regulate alternative splicing. KEYWORDSPre-mRNA splicing; regulation of pre-mRNA splicing; remodeling of RNAprotein complexes; RNA helicase structure, function and regulation; spliceosome catalytic activation

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Section: Brr2 Regulation In the Tri-snrnpsupporting

confidence: 53%

Section: Brr2 Requires Tight Regulationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Functions and regulation of the Brr2 RNA helicase during splicing

2016

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Spliceosomopathies and neurocristopathies: Two sides of the same coin?

Beauchamp

Alam

Kumar

et al. 2020

Developmental Dynamics

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Mutations in core components of the spliceosome are responsible for a group of syndromes collectively known as spliceosomopathies. Patients exhibit microcephaly, micrognathia, malar hypoplasia, external ear anomalies, eye anomalies, psychomotor delay, intellectual disability, limb, and heart defects. Craniofacial malformations in these patients are predominantly found in neural crest cells‐derived structures of the face and head. Mutations in eight genes SNRPB, RNU4ATAC, SF3B4, PUF60, EFTUD2, TXNL4, EIF4A3, and CWC27 are associated with craniofacial spliceosomopathies. In this review, we provide a brief description of the normal development of the head and the face and an overview of mutations identified in genes associated with craniofacial spliceosomopathies. We also describe a model to explain how and when these mutations are most likely to impact neural crest cells. We speculate that mutations in a subset of core splicing factors lead to disrupted splicing in neural crest cells because these cells have increased sensitivity to inefficient splicing. Hence, disruption in splicing likely activates a cellular stress response that includes increased skipping of regulatory exons in genes such as MDM2 and MDM4, key regulators of P53. This would result in P53‐associated death of neural crest cells and consequently craniofacial malformations associated with spliceosomopathies.

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TXNL4B regulates radioresistance by controlling the PRP3‐mediated alternative splicing of FANCI

Zhao

Jing

Xiao

et al. 2023

MedComm

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Ionizing radiation (IR) has been extensively used for cancer therapy, but the radioresistance hinders and undermines the radiotherapy efficacy in clinics greatly. Here, we reported that the spliceosomal protein thioredoxin‐like 4B (TXNL4B) is highly expressed in lung tissues from lung cancer patients with radiotherapy. Lung cancer cells with TXNL4B knockdown illustrate increased sensitivity to IR. Mechanistically, TXNL4B interacts with RNA processing factor 3 (PRP3) and co‐localizes in the nucleus post‐IR. Nuclear localization of PRP3 promotes the alternative splicing of the Fanconi anemia group I protein (FANCI) transcript variants, FANCI‐12 and FANCI‐13. PRP3 regulates alternative splicing of FANCI toward the two variants, FANCI‐12 and FANCI‐13. Radioresistance was greatly enhanced through the combination of PRP31 and PRP8, the critical components of core spliceosome promoted by PRP3. Notably, the inhibition of PRP3 to suppress the production of FANCI‐12 would deprive PRP31 and PRP8 of such interaction. As a result, cell cycle G2/M arrest was induced, DNA damage repair was delayed, and radiosensitivity was improved. Collectively, our study highlights potential novel underlying mechanisms of the involvement of TXNL4B and alternative splicing in radioresistance. The results would benefit potential cancer radiotherapy.

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Molecular architecture of the human U4/U6.U5 tri-snRNP

Cited by 180 publications

References 52 publications

Functions and regulation of the Brr2 RNA helicase during splicing

Functions and regulation of the Brr2 RNA helicase during splicing

Spliceosomopathies and neurocristopathies: Two sides of the same coin?

TXNL4B regulates radioresistance by controlling the PRP3‐mediated alternative splicing of FANCI

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