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

ABSTRACT: Nuclear factor kappa B (NF-?B) 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-?B activation and induction of Bcl-xL. However, Pacs-2 was not required for tumor necrosis factor-?-induced NF-?B activation, suggesting a role for PACS-2 selectively in NF-?B activation in response to DNA damage. These findings identify PACS-2 as an in vivo mediator of the ATM and NF-?B-dependent induction of Bcl-xL that promotes cell survival in response to DNA damage.

SUBMITTER: Barroso-Gonzalez J 

PROVIDER: S-EPMC5072422 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature