The cancer-associated U2AF35 470A>G (Q157R) mutation creates an in-frame alternative 5′ splice site that impacts splicing regulation in Q157R patients
- 1Freie Universität Berlin, Institute of Chemistry and Biochemistry, Laboratory of RNA Biochemistry, 14195 Berlin, Germany
- 2Sequencing Core Facility, Max-Planck-Institute for Molecular Genetics, 14195 Berlin, Germany
- Corresponding author: florian.heyd{at}fu-berlin.de
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↵3These authors contributed equally to this work.
Abstract
Recent work has identified cancer-associated U2AF35 missense mutations in two zinc-finger (ZnF) domains, but little is known about Q157R/P substitutions within the second ZnF. Surprisingly, we find that the c.470A>G mutation not only leads to the Q157R substitution, but also creates an alternative 5′ splice site (ss) resulting in the deletion of four amino acids (Q157Rdel). Q157P, Q157R, and Q157Rdel control alternative splicing of distinct groups of exons in cell culture and in human patients, suggesting that missplicing of different targets may contribute to cellular aberrations. Our data emphasize the importance to explore missense mutations beyond altered protein sequence.
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Article is online at http://www.rnajournal.org/cgi/doi/10.1261/rna.061432.117.
- Received March 22, 2017.
- Accepted September 5, 2017.
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