GSK3? negatively regulates TRAX, a scaffold protein implicated in mental disorders, for NHEJ-mediated DNA repair in neurons.

ABSTRACT: Translin-associated protein X (TRAX) is a scaffold protein with various functions and has been associated with mental illnesses, including schizophrenia. We have previously demonstrated that TRAX interacts with a Gs? protein-coupled receptor, the A2A adenosine receptor (A2AR), and mediates the function of this receptor in neuritogenesis. In addition, stimulation of the A2AR markedly ameliorates DNA damage evoked by elevated oxidative stress in neurons derived from induced pluripotent stem cells (iPSCs). Here, we report that glycogen synthase kinase 3 beta (GSK3?) and disrupted-in-schizophrenia 1 (DISC1) are two novel interacting proteins of TRAX. We present evidence to suggest that the stimulation of A2AR markedly facilitated DNA repair through the TRAX/DISC1/GSK3? complex in a rat neuronal cell line (PC12), primary mouse neurons, and human medium spiny neurons derived from iPSCs. A2AR stimulation led to the inhibition of GSK3?, thus dissociating the TRAX/DISC1/GSK3? complex and facilitating the non-homologous end-joining pathway (NHEJ) by enhancing the activation of a DNA-dependent protein kinase via phosphorylation at Thr2609. Similarly, pharmacological inhibition of GSK3? by SB216763 also facilitated the TRAX-mediated repair of oxidative DNA damage. Collectively, GSK3? binds with TRAX and negatively affects its ability to facilitate NHEJ repair. The suppression of GSK3? by A2AR activation or a GSK3? inhibitor releases TRAX for the repair of oxidative DNA damage. Our findings shed new light on the molecular mechanisms underlying diseases associated with DNA damage and provides a novel target (i.e., the TRAX/DISC1/GSK3? complex) for future therapeutic development for mental disorders.

SUBMITTER: Chien T 

PROVIDER: S-EPMC6294740 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature