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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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