Thymine DNA Glycosylase Promotes Wnt/β-catenin Signaling

The highly conserved Wnt/β-catenin signaling controls diverse biological processes such as cell fate decision, tumorigenesis, and stem cell pluripotency. In this work, a novel function of Thymine DNA Glycosylase (TDG) was found to work as a coactivator in Wnt signaling through cooperating with CBP.

Under the supervision of Prof. LI Lin from the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Dr. JIA Yingying and colleagues provide evidence to demonstrate a new role of TDG involved in Wnt signaling. TDG directly binds to TCFs and promotes the Wnt target genes expression. Further mechanistic studies show that the function of TDG in Wnt signaling is dependent on another coactivator CBP. TDG form a quaternary complex with β-catenin/TCFs and CBP via multiple intermolecular interactions, which subsequently stabilize these factors on the Wnt target gene promoters. This quaternary complex promotes Histone 4 acetylation and facilitates the β-catenin/TCFs transactivation activity. In addition, elevated TDG protein levels are found in human colon cancer tissues. In colon cancer HCT116 and SW620 cells, TDG knockdown could reduce the Wnt target genes expression and cell growth.

This study entitled “Thymine DNA glycosylase promotes transactivation of β-catenin/TCFs by cooperating with CBP” was published online in Journal of Molecular Cell Biology on April 18, 2014. This work was supported by grants from the Ministry of Science and Technology of China, the National Natural Science Foundation of China, and the Young Scientist grant of Shanghai Institutes for Biological Sciences.

A model for activation of Wnt target genes by the endogenous complex composed of β-catenin, TCFs, TDG and CBP. (Image provided by Prof. LI Lin’s group).