How Is Precursor Messenger RNA Spliced by the Spliceosome?

2020 ◽  
Vol 89 (1) ◽  
pp. 333-358 ◽  
Author(s):  
Ruixue Wan ◽  
Rui Bai ◽  
Xiechao Zhan ◽  
Yigong Shi
Keyword(s):  
Active Site ◽  
Rna Splicing ◽  
Messenger Rna ◽  
Small Nuclear Rna ◽  
Exon Ligation ◽  
Nuclear Rna ◽  
Catalytic Metal ◽  
Protein Components ◽  
Intron Removal ◽  
Duplex Formation

Splicing of the precursor messenger RNA, involving intron removal and exon ligation, is mediated by the spliceosome. Together with biochemical and genetic investigations of the past four decades, structural studies of the intact spliceosome at atomic resolution since 2015 have led to mechanistic delineation of RNA splicing with remarkable insights. The spliceosome is proven to be a protein-orchestrated metalloribozyme. Conserved elements of small nuclear RNA (snRNA) constitute the splicing active site with two catalytic metal ions and recognize three conserved intron elements through duplex formation, which are delivered into the splicing active site for branching and exon ligation. The protein components of the spliceosome stabilize the conformation of the snRNA, drive spliceosome remodeling, orchestrate the movement of the RNA elements, and facilitate the splicing reaction. The overall organization of the spliceosome and the configuration of the splicing active site are strictly conserved between human and yeast.

RNA Splicing by the Spliceosome

2020 ◽  
Vol 89 (1) ◽  
pp. 359-388 ◽  
Author(s):  
Max E. Wilkinson ◽  
Clément Charenton ◽  
Kiyoshi Nagai
Keyword(s):  
Splice Site ◽  
Active Site ◽  
Rna Splicing ◽  
Messenger Rna ◽  
Structural Studies ◽  
U2 Snrna ◽  
U6 Snrna ◽  
Mature Mrna ◽  
Catalytic Metal ◽  
Small Nuclear Ribonucleoproteins

The spliceosome removes introns from messenger RNA precursors (pre-mRNA). Decades of biochemistry and genetics combined with recent structural studies of the spliceosome have produced a detailed view of the mechanism of splicing. In this review, we aim to make this mechanism understandable and provide several videos of the spliceosome in action to illustrate the intricate choreography of splicing. The U1 and U2 small nuclear ribonucleoproteins (snRNPs) mark an intron and recruit the U4/U6.U5 tri-snRNP. Transfer of the 5′ splice site (5′SS) from U1 to U6 snRNA triggers unwinding of U6 snRNA from U4 snRNA. U6 folds with U2 snRNA into an RNA-based active site that positions the 5′SS at two catalytic metal ions. The branch point (BP) adenosine attacks the 5′SS, producing a free 5′ exon. Removal of the BP adenosine from the active site allows the 3′SS to bind, so that the 5′ exon attacks the 3′SS to produce mature mRNA and an excised lariat intron.

scholarly journals Analysis of aberrant pre-messenger RNA splicing resulting from mutations inATP8B1and efficientin vitrorescue by adapted U1 small nuclear RNA

Hepatology ◽  
2015 ◽  
Vol 61 (4) ◽  
pp. 1382-1391 ◽  
Author(s):  
Wendy L. van der Woerd ◽  
Johanna Mulder ◽  
Franco Pagani ◽  
Ulrich Beuers ◽  
Roderick H.J. Houwen ◽  
...  
Keyword(s):  
Rna Splicing ◽  
Messenger Rna ◽  
Small Nuclear Rna ◽  
Nuclear Rna

scholarly journals Novel models for RNA splicing that involve a small nuclear RNA.

1981 ◽  
Vol 78 (7) ◽  
pp. 4471-4474 ◽  
Author(s):  
Y. Ohshima ◽  
M. Itoh ◽  
N. Okada ◽  
T. Miyata
Keyword(s):  
Rna Splicing ◽  
Small Nuclear Rna ◽  
Nuclear Rna

scholarly journals Structures of the Human Spliceosomes Before and After Release of the Ligated Exon

2018 ◽  
Author(s):  
Xiaofeng Zhang ◽  
Xiechao Zhan ◽  
Chuangye Yan ◽  
Wenyu Zhang ◽  
Dongliang Liu ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Splice Site ◽  
Mrna Splicing ◽  
Small Nuclear Rna ◽  
Exon Ligation ◽  
Cryo Electron Microscopy ◽  
Branch Point Sequence ◽  
Nuclear Rna ◽  
Before And After ◽  
Functional States

Pre-mRNA splicing is executed by the spliceosome, which has eight major functional states each with distinct composition. Five of these eight human spliceosomal complexes, all preceding exon ligation, have been structurally characterized. In this study, we report the cryo-electron microscopy structures of the human post-catalytic spliceosome (P complex) and intron lariat spliceosome (ILS) at average resolutions of 3.0 and 2.9 Å, respectively. In the P complex, the ligated exon remains anchored to loop I of U5 small nuclear RNA, and the 3'-splice site is recognized by the junction between the 5'-splice site and the branch point sequence. The ATPase/helicase Prp22, along with the ligated exon and eight other proteins, are dissociated in the P-to-ILS transition. Intriguingly, the ILS complex exists in two distinct conformations, one with the ATPase/helicase Prp43 and one without. Comparison of these three late-stage human spliceosomes reveals mechanistic insights into exon release and spliceosome disassembly.

Roles of the U5 snRNP in spliceosome dynamics and catalysis

2004 ◽  
Vol 32 (6) ◽  
pp. 928-931 ◽  
Author(s):  
I.A. Turner ◽  
C.M. Norman ◽  
M.J. Churcher ◽  
A.J. Newman
Keyword(s):  
Mrna Splicing ◽  
Small Nuclear Rna ◽  
Protein Coding ◽  
Rna Molecules ◽  
Small Nuclear Ribonucleoprotein ◽  
Associated Proteins ◽  
Gene Transcripts ◽  
Protein Components ◽  
Intron Removal ◽  
Nuclear Ribonucleoprotein

Most protein-coding genes in eukaryotes are interrupted by non-coding intervening sequences (introns), which must be precisely removed from primary gene transcripts (pre-mRNAs) before translation of the message into protein. Intron removal by pre-mRNA splicing occurs in the nucleus and is catalysed by complex ribonucleoprotein machines called spliceosomes. These molecular machines consist of several small nuclear RNA molecules and their associated proteins [together termed snRNP (small nuclear ribonucleoprotein) particles], plus multiple accessory factors. Of particular interest are the U2, U5 and U6 snRNPs, which play crucial roles in the catalytic steps of splicing. In the present review, we summarize our current understanding of the role played by the protein components of the U5 snRNP in pre-mRNA splicing, which include some of the largest and most highly conserved nuclear proteins.

Compensatory mutations suggest that base-pairing with a small nuclear RNA is required to form the 3′ end of H3 messenger RNA

Nature ◽  
1986 ◽  
Vol 323 (6091) ◽  
pp. 777-781 ◽  
Author(s):  
Fred Schaufele ◽  
Gregory M. Gilmartin ◽  
Willi Bannwarth ◽  
Max L. Birnstiel
Keyword(s):  
Messenger Rna ◽  
Small Nuclear Rna ◽  
Base Pairing ◽  
Nuclear Rna ◽  
Compensatory Mutations
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