Synergistic roles for human U1 snRNA stem-loops in pre-mRNA splicing

Martelly, William; Fellows, Bernice; Kang, Paul; Vashisht, Ajay A.; Wohlschlegel, James A.; Sharma, Shalini

doi:10.1080/15476286.2021.1932360

Cited by 15 publications

(24 citation statements)

References 79 publications

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“…In addition, the unwinding seen in the upper part of the stem suggests the possibility that a helicase is involved. Candidates for this activity might be UAP56 (DHX39B), which is present in the earliest complexes (Fleckner et al , 1997 ; Shen et al , 2008 ) and has also been found to interact with SL3 (Martelly et al , 2021 ), or DDX5, which is involved in the use of 5′SS and U1 snRNP binding or dissociation (Liu, 2002 ; Guil et al , 2003 ; Lin et al , 2005a ; Kar et al , 2011 ). SRSF7 and SRSF9 show similar cross‐linking distributions on U1 snRNA, which suggests that they may also interact with SL3 (Appendix Fig S10 ).…”

Section: Discussionmentioning

confidence: 99%

Exon‐independent recruitment of SRSF1 is mediated by U1 snRNP stem‐loop 3

et al. 2021

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SRSF1 protein and U1 snRNPs are closely connected splicing factors. They both stimulate exon inclusion, SRSF1 by binding to exonic splicing enhancer sequences (ESEs) and U1 snRNPs by binding to the downstream 5 0 splice site (SS), and both factors affect 5 0 SS selection. The binding of U1 snRNPs initiates spliceosome assembly, but SR proteins such as SRSF1 can in some cases substitute for it. The mechanistic basis of this relationship is poorly understood. We show here by single-molecule methods that a single molecule of SRSF1 can be recruited by a U1 snRNP. This reaction is independent of exon sequences and separate from the U1-independent process of binding to an ESE. Structural analysis and cross-linking data show that SRSF1 contacts U1 snRNA stem-loop 3, which is required for splicing. We suggest that the recruitment of SRSF1 to a U1 snRNP at a 5 0 SS is the basis for exon definition by U1 snRNP and might be one of the principal functions of U1 snRNPs in the core reactions of splicing in mammals.

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Section: Discussionmentioning

confidence: 99%

Exon‐independent recruitment of SRSF1 is mediated by U1 snRNP stem‐loop 3

et al. 2021

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“…(c) Model for exon independent recruitment of SRSF1 by U1 snRNP [ 98 ]. (d) Model for UAP56 mediated splicing enhancement [ 100 ]. (e) Crystal structure of SF3A1-UBL (cyan) in complex with U1 snRNA SL4 (grey) (pdb code: 7P0V) [ 108 ].…”

Section: Stabilization Of U1 Snrnp On Weak 5’-splice Sites ...mentioning

confidence: 99%

“…3b ). Mutations in U1 snRNA SL3 are known to disrupt splicing events, highlighting the functional significance of SL3 in the context of U1 snRNP [ 100 ]. In the next paragraphs, we provide examples of interactions between the U1 snRNA SL3 and protein partners and discuss how they contribute to 5ʹss selection or spliceosome assembly.…”

Section: Stabilization Of U1 Snrnp On Weak 5’-splice Sites ...mentioning

confidence: 99%

“…During spliceosome assembly, the transition from the spliceosomal E complex to the A complex can also be promoted by U1 snRNA SL3 interaction with the 56 kDa U2AF65-Associated Protein (UAP56), a DExD/H-box family RNA helicase involved in mRNA nuclear export and pre-spliceosome assembly. U1 snRNA SL3 interacts with UAP56 in an ATP-dependent manner, facilitating contact between U1 and U2 snRNP and the conversion to the spliceosomal A complex [ 100 ] ( Fig. 5d ).…”

Section: Stabilization Of U1 Snrnp On Weak 5’-splice Sites ...mentioning

confidence: 99%

“…Addition of excess free SL3 in trans enhances splicing upon binding to endogenous UAP56 [ 100 ]. UAP56 knockdown or U1 snRNA SL3 mutations are phenotypically equivalent, which results in reduction of exon inclusion and lowered splicing efficiency [ 100 ]. The helicase activity of UAP56 may also facilitate the melting of SL3 and the binding of SRSF1.…”

Section: Stabilization Of U1 Snrnp On Weak 5’-splice Sites ...mentioning

confidence: 99%

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Principles and correction of 5’-splice site selection

2022

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In Eukarya, immature mRNA transcripts (pre-mRNA) often contain coding sequences, or exons, interleaved by non-coding sequences, or introns. Introns are removed upon splicing , and further regulation of the retained exons leads to alternatively spliced mRNA. The splicing reaction requires the stepwise assembly of the spliceosome, a macromolecular machine composed of small nuclear ribonucleoproteins (snRNPs). This review focuses on the early stage of spliceosome assembly, when U1 snRNP defines each intron 5’-splice site (5ʹss) in the pre-mRNA. We first introduce the splicing reaction and the impact of alternative splicing on gene expression regulation. Thereafter, we extensively discuss splicing descriptors that influence the 5ʹss selection by U1 snRNP, such as sequence determinants, and interactions mediated by U1-specific proteins or U1 small nuclear RNA (U1 snRNA). We also include examples of diseases that affect the 5ʹss selection by U1 snRNP, and discuss recent therapeutic advances that manipulate U1 snRNP 5ʹss selectivity with antisense oligonucleotides and small-molecule splicing switches.

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