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SRSF10 Connects DNA Damage to the Alternative Splicing of Transcripts Encoding Apoptosis, Cell-Cycle Control, and DNA

Lulzim Shkreta1, Johanne Toutant1, Mathieu Durand2

  • 1Département de Microbiologie et d'Infectiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada.

Cell Reports
|November 17, 2016
PubMed

Insights

DNA damage from oxaliplatin alters splicing regulation of Bcl-x by affecting RNA binding proteins like SRSF10. This shift favors the pro-apoptotic Bcl-xS variant, influencing cell fate decisions.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • RNA binding proteins regulate alternative splicing of Bcl-x, controlling pro-death (Bcl-xS) and pro-survival variants.
  • DNA damage, induced by agents like oxaliplatin, increases pro-apoptotic Bcl-xS, but the underlying mechanism is unclear.

Purpose of the Study:

  • To elucidate the mechanism by which DNA damage shifts Bcl-x splicing towards the pro-apoptotic variant.
  • To investigate the role of splicing factor SRSF10 and its interactions with other proteins in response to DNA damage.

Main Methods:

  • Investigated protein-RNA interactions using pre-mRNA from Bcl-x.
  • Analyzed the effects of oxaliplatin on splicing factor binding and phosphorylation.
  • Performed broader analysis of SRSF10 targets in response to DNA damage.

Main Results:

  • Oxaliplatin treatment disrupts the interaction between SRSF10 and hnRNP F/H, and reduces SRSF10/hnRNP K binding to Bcl-x pre-mRNA.
  • Dephosphorylation of SRSF10 correlates with these altered interactions.
  • DNA damage redirects SRSF10 to regulate splicing of genes involved in DNA repair, cell cycle, and apoptosis.

Conclusions:

  • DNA damage alters splicing factor interactions to promote the pro-apoptotic Bcl-xS variant, thereby influencing cell fate.
  • SRSF10 plays a critical role in mediating the splicing response to DNA damage across multiple cellular pathways.
Keywords:
DNA damage responseDNA repairRNA binding proteinsSR proteinsalternative splicingapoptosiscell cyclecell fatehnRNP proteinsoxaliplatinphosphorylationsplicing

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