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@article{1745739,
author = {Kralovicova, J. and Borovska, I. and Kubíčková, Monika and Lukavsky, Peter and Vorechovsky, I.},
article_location = {BASEL},
article_number = {7},
doi = {http://dx.doi.org/10.3390/cancers12071865},
keywords = {Functional genomics; pre-mRNA splicing; 3 ' splice site; mRNA; lariat branch point; PUF60; U2AF2; gel shift assay; differential scanning fluorimetry; cancer; leukemia; driver mutation; exon inclusion},
language = {eng},
issn = {2072-6694},
journal = {Cancers},
title = {Cancer-Associated Substitutions in RNA Recognition Motifs of PUF60 and U2AF65 Reveal Residues Required for Correct Folding and 3 ' Splice-Site Selection},
url = {https://www.mdpi.com/2072-6694/12/7/1865},
volume = {12},
year = {2020}
}
TY - JOUR
ID - 1745739
AU - Kralovicova, J. - Borovska, I. - Kubíčková, Monika - Lukavsky, Peter - Vorechovsky, I.
PY - 2020
TI - Cancer-Associated Substitutions in RNA Recognition Motifs of PUF60 and U2AF65 Reveal Residues Required for Correct Folding and 3 ' Splice-Site Selection
JF - Cancers
VL - 12
IS - 7
SP - 1865
EP - 1865
PB - MDPI
SN - 20726694
KW - Functional genomics
KW - pre-mRNA splicing
KW - 3 ' splice site
KW - mRNA
KW - lariat branch point
KW - PUF60
KW - U2AF2
KW - gel shift assay
KW - differential scanning fluorimetry
KW - cancer
KW - leukemia
KW - driver mutation
KW - exon inclusion
UR - https://www.mdpi.com/2072-6694/12/7/1865
N2 - U2AF65 (U2AF2) and PUF60 (PUF60) are splicing factors important for recruitment of the U2 small nuclear ribonucleoprotein to lariat branch points and selection of 3 ' splice sites (3 ' ss). Both proteins preferentially bind uridine-rich sequences upstream of 3 ' ss via their RNA recognition motifs (RRMs). Here, we examined 36 RRM substitutions reported in cancer patients to identify variants that alter 3 ' ss selection, RNA binding and protein properties. Employing PUF60- and U2AF65-dependent 3 ' ss previously identified by RNA-seq of depleted cells, we found that 43% (10/23) and 15% (2/13) of independent RRM mutations in U2AF65 and PUF60, respectively, conferred splicing defects. At least three RRM mutations increased skipping of internalU2AF2(similar to 9%, 2/23) orPUF60(similar to 8%, 1/13) exons, indicating that cancer-associated RRM mutations can have bothcis- andtrans-acting effects on splicing. We also report residues required for correct folding/stability of each protein and map functional RRM substitutions on to existing high-resolution structures of U2AF65 and PUF60. These results identify new RRM residues critical for 3 ' ss selection and provide relatively simple tools to detect clonal RRM mutations that enhance the mRNA isoform diversity.
ER -
KRALOVICOVA, J., I. BOROVSKA, Monika KUBÍČKOVÁ, Peter LUKAVSKY a I. VORECHOVSKY. Cancer-Associated Substitutions in RNA Recognition Motifs of PUF60 and U2AF65 Reveal Residues Required for Correct Folding and 3 ' Splice-Site Selection. \textit{Cancers}. BASEL: MDPI, 2020, roč.~12, č.~7, s.~1865-1883. ISSN~2072-6694. Dostupné z: https://dx.doi.org/10.3390/cancers12071865.
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