PUF60-activated exons uncover altered 3 ' splice-site selection by germline missense mutations in a single RRM

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F18%3A00497047" target="_blank" >RIV/68378050:_____/18:00497047 - isvavai.cz</a>

Result on the web

<a href="http://dx.doi.org/10.1093/nar/gky389" target="_blank" >http://dx.doi.org/10.1093/nar/gky389</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1093/nar/gky389" target="_blank" >10.1093/nar/gky389</a>

Result language

angličtina

Original language name

PUF60-activated exons uncover altered 3 ' splice-site selection by germline missense mutations in a single RRM

Original language description

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 splicesite and branch-site selection.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10608 - Biochemistry and molecular biology

Project

<a href="/en/project/GBP305%2F12%2FG034" target="_blank" >GBP305/12/G034: Centre for RNA Biology</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2018

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Nucleic Acids Research

ISSN

0305-1048

e-ISSN

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Volume of the periodical

46

Issue of the periodical within the volume

12

Country of publishing house

GB - UNITED KINGDOM

Number of pages

12

Pages from-to

6166-6187

UT code for WoS article

000438397200029

EID of the result in the Scopus database

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