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U2AF1 mutations alter splice site recognition in hematological malignancies

Whole-exome sequencing studies have identified common mutations affecting genes encoding components of the RNA splicing machinery in hematological malignancies. Here, we sought to determine how mutations affecting the 3′ splice site recognition factor U2AF1 alter its normal role in RNA splicing. We...

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Autores principales: Ilagan, Janine O., Ramakrishnan, Aravind, Hayes, Brian, Murphy, Michele E., Zebari, Ahmad S., Bradley, Philip, Bradley, Robert K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317169/
https://www.ncbi.nlm.nih.gov/pubmed/25267526
http://dx.doi.org/10.1101/gr.181016.114
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author Ilagan, Janine O.
Ramakrishnan, Aravind
Hayes, Brian
Murphy, Michele E.
Zebari, Ahmad S.
Bradley, Philip
Bradley, Robert K.
author_facet Ilagan, Janine O.
Ramakrishnan, Aravind
Hayes, Brian
Murphy, Michele E.
Zebari, Ahmad S.
Bradley, Philip
Bradley, Robert K.
author_sort Ilagan, Janine O.
collection PubMed
description Whole-exome sequencing studies have identified common mutations affecting genes encoding components of the RNA splicing machinery in hematological malignancies. Here, we sought to determine how mutations affecting the 3′ splice site recognition factor U2AF1 alter its normal role in RNA splicing. We find that U2AF1 mutations influence the similarity of splicing programs in leukemias, but do not give rise to widespread splicing failure. U2AF1 mutations cause differential splicing of hundreds of genes, affecting biological pathways such as DNA methylation (DNMT3B), X chromosome inactivation (H2AFY), the DNA damage response (ATR, FANCA), and apoptosis (CASP8). We show that U2AF1 mutations alter the preferred 3′ splice site motif in patients, in cell culture, and in vitro. Mutations affecting the first and second zinc fingers give rise to different alterations in splice site preference and largely distinct downstream splicing programs. These allele-specific effects are consistent with a computationally predicted model of U2AF1 in complex with RNA. Our findings suggest that U2AF1 mutations contribute to pathogenesis by causing quantitative changes in splicing that affect diverse cellular pathways, and give insight into the normal function of U2AF1’s zinc finger domains.
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spelling pubmed-43171692015-02-05 U2AF1 mutations alter splice site recognition in hematological malignancies Ilagan, Janine O. Ramakrishnan, Aravind Hayes, Brian Murphy, Michele E. Zebari, Ahmad S. Bradley, Philip Bradley, Robert K. Genome Res Research Whole-exome sequencing studies have identified common mutations affecting genes encoding components of the RNA splicing machinery in hematological malignancies. Here, we sought to determine how mutations affecting the 3′ splice site recognition factor U2AF1 alter its normal role in RNA splicing. We find that U2AF1 mutations influence the similarity of splicing programs in leukemias, but do not give rise to widespread splicing failure. U2AF1 mutations cause differential splicing of hundreds of genes, affecting biological pathways such as DNA methylation (DNMT3B), X chromosome inactivation (H2AFY), the DNA damage response (ATR, FANCA), and apoptosis (CASP8). We show that U2AF1 mutations alter the preferred 3′ splice site motif in patients, in cell culture, and in vitro. Mutations affecting the first and second zinc fingers give rise to different alterations in splice site preference and largely distinct downstream splicing programs. These allele-specific effects are consistent with a computationally predicted model of U2AF1 in complex with RNA. Our findings suggest that U2AF1 mutations contribute to pathogenesis by causing quantitative changes in splicing that affect diverse cellular pathways, and give insight into the normal function of U2AF1’s zinc finger domains. Cold Spring Harbor Laboratory Press 2015-01 /pmc/articles/PMC4317169/ /pubmed/25267526 http://dx.doi.org/10.1101/gr.181016.114 Text en © 2015 Ilagan et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research
Ilagan, Janine O.
Ramakrishnan, Aravind
Hayes, Brian
Murphy, Michele E.
Zebari, Ahmad S.
Bradley, Philip
Bradley, Robert K.
U2AF1 mutations alter splice site recognition in hematological malignancies
title U2AF1 mutations alter splice site recognition in hematological malignancies
title_full U2AF1 mutations alter splice site recognition in hematological malignancies
title_fullStr U2AF1 mutations alter splice site recognition in hematological malignancies
title_full_unstemmed U2AF1 mutations alter splice site recognition in hematological malignancies
title_short U2AF1 mutations alter splice site recognition in hematological malignancies
title_sort u2af1 mutations alter splice site recognition in hematological malignancies
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317169/
https://www.ncbi.nlm.nih.gov/pubmed/25267526
http://dx.doi.org/10.1101/gr.181016.114
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