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

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 general

SUBMITTER: Vigevani L 

PROVIDER: S-EPMC5727392 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature