PUF60-activated exons uncover altered 3' splice-site selection by germline missense mutations in a single RRM
Jazyk angličtina Země Anglie, Velká Británie Médium print
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
Wellcome Trust - United Kingdom
PubMed
29788428
PubMed Central
PMC6093180
DOI
10.1093/nar/gky389
PII: 4999237
Knihovny.cz E-zdroje
- MeSH
- aminokyselinové motivy MeSH
- exony * MeSH
- HEK293 buňky MeSH
- HeLa buňky MeSH
- heterogenní jaderné ribonukleoproteiny metabolismus MeSH
- jaderné proteiny metabolismus MeSH
- krátké rozptýlené jaderné elementy MeSH
- lidé MeSH
- malý jaderný ribonukleoprotein U1 metabolismus MeSH
- missense mutace * MeSH
- místa sestřihu RNA * MeSH
- proteiny vázající RNA metabolismus MeSH
- represorové proteiny chemie nedostatek metabolismus MeSH
- sekvenční analýza RNA MeSH
- sestřihové faktory chemie nedostatek metabolismus MeSH
- sestřihový faktor U2AF MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- HCC1 autoantigen MeSH Prohlížeč
- heterogenní jaderné ribonukleoproteiny MeSH
- jaderné proteiny MeSH
- malý jaderný ribonukleoprotein U1 MeSH
- místa sestřihu RNA * MeSH
- poly-U binding splicing factor 60KDa MeSH Prohlížeč
- proteiny vázající RNA MeSH
- represorové proteiny MeSH
- sestřihové faktory MeSH
- sestřihový faktor U2AF MeSH
- SNRNP70 protein, human MeSH Prohlížeč
PUF60 is a splicing factor that binds uridine (U)-rich tracts and facilitates association of the U2 small nuclear ribonucleoprotein with primary transcripts. PUF60 deficiency (PD) causes a developmental delay coupled with intellectual disability and spinal, cardiac, ocular and renal defects, but PD pathogenesis is not understood. Using RNA-Seq, we identify human PUF60-regulated exons and show that PUF60 preferentially acts as their activator. PUF60-activated internal exons are enriched for Us upstream of their 3' splice sites (3'ss), are preceded by longer AG dinucleotide exclusion zones and more distant branch sites, with a higher probability of unpaired interactions across a typical branch site location as compared to control exons. In contrast, PUF60-repressed exons show U-depletion with lower estimates of RNA single-strandedness. We also describe PUF60-regulated, alternatively spliced isoforms encoding other U-bound splicing factors, including PUF60 partners, suggesting that they are co-regulated in the cell, and identify PUF60-regulated exons derived from transposed elements. PD-associated amino-acid substitutions, even within a single RNA recognition motif (RRM), altered selection of competing 3'ss and branch points of a PUF60-dependent exon and the 3'ss choice was also influenced by alternative splicing of PUF60. Finally, we propose that differential distribution of RNA processing steps detected in cells lacking PUF60 and the PUF60-paralog RBM39 is due to the RBM39 RS domain interactions. Together, these results provide new insights into regulation of exon usage by the 3'ss organization and reveal that germline mutation heterogeneity in RRMs can enhance phenotypic variability at the level of splice-site and branch-site selection.
Czech Academy of Sciences Institute of Molecular Genetics 142 20 Prague Czech Republic
Slovak Academy of Sciences Centre for Biosciences 840 05 Bratislava Slovak Republic
University of Southampton Faculty of Medicine Southampton SO16 6YD UK
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Restriction of an intron size en route to endothermy