| Summary: | 博士 === 國防醫學院 === 生命科學研究所 === 106 === Translin-associated protein X (TRAX) is a scaffold protein with various cellular
functions and has been implicated in mental disorders. It interacts specifically
with an activator (i.e., C1D) of DNA- dependent protein kinase (DNA-PK) upon
γ-irradiation and thus is implicated in repair of double-strand breaks (DSBs).
We previously found that TRAX is an interacting protein of the cytoplasmic C
terminus of A2AR, is a G protein-coupled receptor that binds to adenosine and
exists in many brain areas. In addition, we also reported that TRAX interacts
with phosphorylated ATM (Ser1981) and contributes to the ATM-mediated DNA
repair in response to genotoxic stresses. Given that stimulation of A2AR by
A2AR-selective agonist (CGS21680) markedly ameliorates the DNA damage
and apoptosis evoked by elevated oxidative stress in human iPSCs-derived
neurons, the role of TRAX in mediating the protective role of A2AR is of great
interest. In the present study, we demonstrated that glycogen synthase kinase
3 beta (GSK3β) and disrupted in schizophrenia 1 (DISC1) are two novel
interacting protein of TRAX. Here, we present evidence to suggest that
A2AR-mediated enhancement of DNA repair via inhibition of GSK3β to
dissociate the TRAX/DISC1/GSK3β (TDG) complex in a rat neuronal cell line
(PC12), primary mouse neurons, and human medium spiny
neurons (MSNs)-like neurons. Most intriguingly, inhibition of GSK3β by
activation of A2AR releases TRAX from the complex to the nucleus. Moreover,
stimulation of A2AR might facilitate the non-homologous end joining (NHEJ)
repair activity by increasing the nucleocytoplasmic shuttling of TRAX into the
nucleus to activate DNA-dependent protein kinase (DNA-PK) by
phosphorylation at Thr2609. Together, GSK3β binds with TRAX and negatively
affects its ability to enhance NHEJ repair. Similarly, in addition to stimulation of
A2AR, the suppression of GSK3β by GSK3β inhibitor (SB216763) also
facilitated the TRAX-mediated repair to increase the level of TRAX in the
nucleus. Collectively our findings shed new light on the molecular mechanisms
underlying disease associated with impaired DNA repair and provides a novel
target (i.e., the TRAX/DISC1/GSK3β complex) for future therapeutic
development for mental disorders.
|
|---|
