Molecular basis of differential 3′ splice site sensitivity to anti-tumor drugs targeting U2 snRNP

Luisa Vigevani, André Gohr, Thomas Webb, Manuel Irimia and Juan Valcárcel ()
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Luisa Vigevani: The Barcelona Institute of Science and Technology
André Gohr: The Barcelona Institute of Science and Technology
Thomas Webb: SRI International
Manuel Irimia: The Barcelona Institute of Science and Technology
Juan Valcárcel: The Barcelona Institute of Science and Technology

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract Several splicing-modulating compounds, including Sudemycins and Spliceostatin A, display anti-tumor properties. Combining transcriptome, bioinformatic and mutagenesis analyses, we delineate sequence determinants of the differential sensitivity of 3′ splice sites to these drugs. Sequences 5′ from the branch point (BP) region strongly influence drug sensitivity, with additional functional BPs reducing, and BP-like sequences allowing, drug responses. Drug-induced retained introns are typically shorter, displaying higher GC content and weaker polypyrimidine-tracts and BPs. Drug-induced exon skipping preferentially affects shorter alternatively spliced regions with weaker BPs. Remarkably, structurally similar drugs display both common and differential effects on splicing regulation, SSA generally displaying stronger effects on intron retention, and Sudemycins more acute effects on exon skipping. Collectively, our results illustrate how splicing modulation is exquisitely sensitive to the sequence context of 3′ splice sites and to small structural differences between drugs.

Date: 2017
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DOI: 10.1038/s41467-017-02007-z

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