GSK3β negatively regulates TRAX, a scaffold protein implicated in mental disorders, for NHEJ-mediated DNA repair in neurons

被引:24
作者
Chien, Ting [1 ,2 ]
Weng, Yu-Ting [2 ,4 ,5 ]
Chang, Shu-Yung [2 ,3 ]
Lai, Hsing-Lin [2 ]
Chiu, Feng-Lan [6 ]
Kuo, Hung-Chih [6 ]
Chuang, De-Maw [7 ]
Chern, Yijuang [1 ,2 ,3 ,4 ,5 ]
机构
[1] Natl Def Med Ctr, Grad Inst Life Sci, Taipei, Taiwan
[2] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan
[3] Natl Yang Ming Univ, Inst Neurosci, Taipei, Taiwan
[4] Natl Yang Ming Univ, Program Mol Med, Taipei, Taiwan
[5] Acad Sinica, Taipei, Taiwan
[6] Acad Sinica, Inst Cellular & Organism Biol, Taipei, Taiwan
[7] NIMH, Intramural Res Program, NIH, Bethesda, MD 20892 USA
关键词
A(2A) ADENOSINE RECEPTOR; HUNTINGTONS-DISEASE; BIPOLAR DISORDER; OXIDATIVE STRESS; MITOCHONDRIAL DYSFUNCTION; P53; BLOCKAGE; SCHIZOPHRENIA; TRANSLIN; LITHIUM; DAMAGE;
D O I
10.1038/s41380-017-0007-z
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 alpha protein-coupled receptor, the A(2A) adenosine receptor (A(2A)R), and mediates the function of this receptor in neuritogenesis. In addition, stimulation of the A(2A)R 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 beta) and disrupted-inschizophrenia 1 (DISC1) are two novel interacting proteins of TRAX. We present evidence to suggest that the stimulation of A(2A)R markedly facilitated DNA repair through the TRAX/DISC1/GSK3 beta complex in a rat neuronal cell line (PC12), primary mouse neurons, and human medium spiny neurons derived from iPSCs. A(2A)R stimulation led to the inhibition of GSK3 beta, thus dissociating the TRAX/DISC1/GSK3 beta complex and facilitating the non-homologous end-joining pathway (NHEJ) by enhancing the activation of a DNA-dependent protein kinase via phosphorylation at Thr(2609). Similarly, pharmacological inhibition of GSK3 beta by SB216763 also facilitated the TRAX-mediated repair of oxidative DNA damage. Collectively, GSK3 beta binds with TRAX and negatively affects its ability to facilitate NHEJ repair. The suppression of GSK3 beta by A(2A)R activation or a GSK3 beta 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 beta complex) for future therapeutic development for mental disorders.
引用
收藏
页码:2375 / 2390
页数:16
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