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

Cell Rep. 2016 Nov 15;17(8):1990-2003. doi: 10.1016/j.celrep.2016.10.071.

Abstract

RNA binding proteins and signaling components control the production of pro-death and pro-survival splice variants of Bcl-x. DNA damage promoted by oxaliplatin increases the level of pro-apoptotic Bcl-xS in an ATM/CHK2-dependent manner, but how this shift is enforced is not known. Here, we show that in normally growing cells, when the 5' splice site of Bcl-xS is largely repressed, SRSF10 partially relieves repression and interacts with repressor hnRNP K and stimulatory hnRNP F/H proteins. Oxaliplatin abrogates the interaction of SRSF10 with hnRNP F/H and decreases the association of SRSF10 and hnRNP K with the Bcl-x pre-mRNA. Dephosphorylation of SRSF10 is linked with these changes. A broader analysis reveals that DNA damage co-opts SRSF10 to control splicing decisions in transcripts encoding components involved in DNA repair, cell-cycle control, and apoptosis. DNA damage therefore alters the interactions between splicing regulators to elicit a splicing response that determines cell fate.

Keywords: DNA damage response; DNA repair; RNA binding proteins; SR proteins; alternative splicing; apoptosis; cell cycle; cell fate; hnRNP proteins; oxaliplatin; phosphorylation; splicing.

MeSH terms

  • Alternative Splicing / drug effects
  • Alternative Splicing / genetics*
  • Apoptosis / drug effects
  • Apoptosis / genetics*
  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Checkpoints / genetics*
  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • DNA Damage / genetics*
  • DNA Repair / drug effects
  • DNA Repair / genetics*
  • Heterogeneous-Nuclear Ribonucleoproteins / metabolism
  • Humans
  • Models, Biological
  • Organoplatinum Compounds / pharmacology
  • Oxaliplatin
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • RNA Precursors / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Repressor Proteins / metabolism*
  • Serine-Arginine Splicing Factors / metabolism*
  • bcl-X Protein / genetics

Substances

  • Cell Cycle Proteins
  • Heterogeneous-Nuclear Ribonucleoproteins
  • Organoplatinum Compounds
  • RNA Precursors
  • RNA, Messenger
  • Repressor Proteins
  • SRSF10 protein, human
  • bcl-X Protein
  • Oxaliplatin
  • Serine-Arginine Splicing Factors