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Keywords:

  • alternative splicing;
  • apoptosis;
  • BCL-X;
  • FBI-1;
  • SAM68

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

Thumbnail image of graphical abstract

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.