PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage

J. Barroso-González, S. Auclair, S. Luan, L. Thomas, K. M. Atkins, Joseph Aslan, L. L. Thomas, J. Zhao, Y. Zhao, G. Thomas

Research output: Contribution to journalArticle

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Abstract

Nuclear factor kappa B (NF-κB) promotes cell survival in response to genotoxic stress by inducing the expression of anti-apoptotic proteins including Bcl-xL, which protects mitochondria from stress-induced mitochondrial outer membrane permeabilization (MOMP). Here we show that the multifunctional sorting protein Pacs-2 (phosphofurin acidic cluster sorting protein-2) is required for Bcl-xL induction following DNA damage in primary mouse thymocytes. Consequently, in response to DNA damage, Pacs-2-/- thymocytes exhibit a blunted induction of Bcl-xL, increased MOMP and accelerated apoptosis. Biochemical studies show that cytoplasmic PACS-2 promotes this DNA damage-induced anti-apoptotic pathway by interacting with ataxia telangiectasia mutated (ATM) to drive NF-κB activation and induction of Bcl-xL. However, Pacs-2 was not required for tumor necrosis factor-α-induced NF-κB activation, suggesting a role for PACS-2 selectively in NF-κB activation in response to DNA damage. These findings identify PACS-2 as an in vivo mediator of the ATM and NF-κB-dependent induction of Bcl-xL that promotes cell survival in response to DNA damage.Cell Death and Differentiation advance online publication, 4 March 2016; doi:10.1038/cdd.2016.23.

Original languageEnglish (US)
JournalCell Death and Differentiation
DOIs
StateAccepted/In press - Mar 4 2016

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Ataxia Telangiectasia
NF-kappa B
DNA Damage
Protein Transport
Mitochondrial Membranes
Thymocytes
Cell Survival
Apoptosis Regulatory Proteins
Publications
Cell Differentiation
Mitochondria
Cell Death
Tumor Necrosis Factor-alpha
Apoptosis

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage. / Barroso-González, J.; Auclair, S.; Luan, S.; Thomas, L.; Atkins, K. M.; Aslan, Joseph; Thomas, L. L.; Zhao, J.; Zhao, Y.; Thomas, G.

In: Cell Death and Differentiation, 04.03.2016.

Research output: Contribution to journalArticle

Barroso-González, J. ; Auclair, S. ; Luan, S. ; Thomas, L. ; Atkins, K. M. ; Aslan, Joseph ; Thomas, L. L. ; Zhao, J. ; Zhao, Y. ; Thomas, G. / PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage. In: Cell Death and Differentiation. 2016.
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