Abstract
Alternative splicing (AS) is tightly coupled to transcription for the majority of human genes. However, how these two processes are linked is not well understood. Here, we unveil a direct role for the transcription factor FBI-1 in the regulation of AS. FBI-1 interacts with the splicing factor SAM68 and reduces its binding to BCL-X mRNA. This, in turn, results in the selection of the proximal 5 splice site in BCL-X exon 2, thereby favoring the anti-apoptotic BCL-XL variant and counteracting SAM68-mediated apoptosis. Conversely, depletion of FBI-1, or expression of a SAM68 mutant lacking the FBI-1 binding region, restores the ability of SAM68 to induce BCL-XS splicing and apoptosis. FBI-1's role in splicing requires the activity of histone deacetylases, whose pharmacological inhibition recapitulates the effects of FBI-1 knockdown. Our study reveals an unexpected function for FBI-1 in splicing modulation with a direct impact on cell survival. Synopsis The oncogenic transcription factor FBI-1 regulates alternative splicing by preventing the splicing regulator SAM68 from binding to BCL-X mRNA. This increases anti-apoptotic BCL-X isoform expression and cell survival. The transcription factor FBI-1 directly interacts with the splicing regulator SAM68. FBI-1 impairs binding of SAM68 to BCL-X mRNA and thus promotes production of the anti-apoptotic BCL-X isoform and cell survival. FBI-1's effect on BCL-X splicing requires histone deacetylase activity. The oncogenic transcription factor FBI-1 regulates alternative splicing by preventing the splicing regulator SAM68 from binding to BCL-X mRNA. This increases anti-apoptotic BCL-X isoform expression and cell survival.
Original language | English |
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Pages (from-to) | 419-427 |
Number of pages | 9 |
Journal | EMBO Reports |
Volume | 15 |
Issue number | 4 |
DOIs | |
Publication status | Published - 2014 |
Keywords
- alternative splicing
- apoptosis
- BCL-X
- FBI-1
- SAM68
ASJC Scopus subject areas
- Genetics
- Molecular Biology
- Biochemistry
- Medicine(all)