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The DNA damage response pathway regulates the alternative splicing of the apoptotic mediator Bcl-x

Lulzim Shkreta1, Laetitia Michelle, Johanne Toutant

  • 1RNA/RNP Group, Département de Microbiologie et d'Infectiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada.

The Journal of Biological Chemistry
|October 29, 2010
PubMed

Insights

Genotoxic stress triggers a DNA damage response, shifting Bcl-x splicing towards the pro-apoptotic variant. This switch, regulated by ATM/CHK2/p53 and tyrosine phosphatases, balances cell survival and death signals.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Cancer Research

Background:

  • Alternative splicing generates protein isoforms with opposing functions, crucial for regulating apoptosis.
  • Protein kinase C (PKC) signaling influences Bcl-x splicing, favoring the anti-apoptotic Bcl-x(L) variant.

Purpose of the Study:

  • To investigate the role of DNA damage response pathways in regulating alternative splicing of Bcl-x.
  • To elucidate the molecular mechanisms by which genotoxic stress influences the balance of pro- and anti-apoptotic Bcl-x splice variants.

Main Methods:

  • Utilized oxaliplatin to induce genotoxic stress in cell models.
  • Investigated the involvement of ATM, CHK2, p53, and protein-tyrosine phosphatases in splicing regulation.
  • Analyzed the role of the SB1 regulatory sequence element in mediating splicing control.
  • Assessed the impact of impaired protein synthesis and proteasome inhibition on splicing.

Main Results:

  • Genotoxic stress induced by oxaliplatin activates an ATM-, CHK2-, and p53-dependent switch favoring pro-apoptotic Bcl-x(S) production.
  • This DNA damage-induced splicing shift requires protein-tyrosine phosphatase activity.
  • The ATM/CHK2/p53/tyrosine phosphatases pathway converges with the PKC pathway at the SB1 regulatory element.
  • SB1-mediated repression is dependent on protein synthesis and proteasomal degradation.

Conclusions:

  • The DNA damage response pathway antagonistically regulates Bcl-x splicing compared to PKC signaling.
  • The SB1 splicing regulatory module integrates signals from both pathways to control the Bcl-x splice variant balance.
  • This mechanism is critical for determining cell fate decisions between survival and apoptosis under genotoxic stress.

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