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hnRNP A1/A2 and Sam68 collaborate with SRSF10 to control the alternative splicing response to oxaliplatin-mediated

Alexandre Cloutier1, Lulzim Shkreta1, Johanne Toutant1

  • 1Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, J1E 4K8, Canada.

Scientific Reports
|February 4, 2018
PubMed

Insights

DNA damage reconfigures RNA binding protein partnerships, altering alternative splicing. Key proteins like SRSF10, hnRNP A1/A2, and Sam68 collaborate to control splicing for apoptosis and DNA repair pathways.

Area of Science:

  • Molecular Biology
  • RNA Biology
  • Cellular Stress Response

Background:

  • RNA binding proteins (RBPs) orchestrate RNA splicing, but their cooperative mechanisms and regulation by stress pathways remain unclear.
  • Previous work identified SRSF10's role in Bcl-x splicing following DNA damage.
  • The Bcl-x gene produces splice variants impacting apoptosis, making its regulation critical for cell fate.

Purpose of the Study:

  • To investigate how RNA binding proteins cooperate in alternative splicing.
  • To understand how DNA damage pathways reconfigure RBP assemblies and alter splice site selection.
  • To identify specific RBPs involved in the DNA damage-induced Bcl-x splicing response.

Main Methods:

  • RNA affinity assays were used to identify proteins interacting with the Bcl-x pre-mRNA.
  • Western blotting and immunoprecipitation were employed to confirm protein interactions.
  • Analysis of alternative splicing patterns under normal and DNA-damaged conditions.

Main Results:

  • SRSF10, 14-3-3ε, hnRNP A1/A2, and Sam68 were identified as key RBPs involved in Bcl-x splicing upon DNA damage.
  • These RBPs, while not critical under normal conditions, become essential for activating the pro-apoptotic Bcl-xS splice site after DNA damage.
  • DNA damage was shown to reconfigure the binding and activity of these RBPs on the Bcl-x pre-mRNA.

Conclusions:

  • DNA damage rewires the splicing factor circuitry, creating new partnerships to regulate alternative splicing.
  • SRSF10, hnRNP A1/A2, and Sam68 collaborate to drive DNA damage-induced splicing of transcripts involved in apoptosis, cell-cycle control, and DNA repair.
  • This rewiring coordinates alternative splicing across crucial cellular processes, impacting cell fate decisions.

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