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SNIP1 Recruits TET2 to Regulate c-MYC Target Genes and Cellular DNA Damage Response.

  • Author(s): Chen, Lei-Lei;
  • Lin, Huai-Peng;
  • Zhou, Wen-Jie;
  • He, Chen-Xi;
  • Zhang, Zhi-Yong;
  • Cheng, Zhou-Li;
  • Song, Jun-Bin;
  • Liu, Peng;
  • Chen, Xin-Yu;
  • Xia, Yu-Kun;
  • Chen, Xiu-Fei;
  • Sun, Ren-Qiang;
  • Zhang, Jing-Ye;
  • Sun, Yi-Ping;
  • Song, Lei;
  • Liu, Bing-Jie;
  • Du, Rui-Kai;
  • Ding, Chen;
  • Lan, Fei;
  • Huang, Sheng-Lin;
  • Zhou, Feng;
  • Liu, Suling;
  • Xiong, Yue;
  • Ye, Dan;
  • Guan, Kun-Liang
  • et al.
Abstract

The TET2 DNA dioxygenase regulates gene expression by catalyzing demethylation of 5-methylcytosine, thus epigenetically modulating the genome. TET2 does not contain a sequence-specific DNA-binding domain, and how it is recruited to specific genomic sites is not fully understood. Here we carried out a mammalian two-hybrid screen and identified multiple transcriptional regulators potentially interacting with TET2. The SMAD nuclear interacting protein 1 (SNIP1) physically interacts with TET2 and bridges TET2 to bind several transcription factors, including c-MYC. SNIP1 recruits TET2 to the promoters of c-MYC target genes, including those involved in DNA damage response and cell viability. TET2 protects cells from DNA damage-induced apoptosis dependending on SNIP1. Our observations uncover a mechanism for targeting TET2 to specific promoters through a ternary interaction with a co-activator and many sequence-specific DNA-binding factors. This study also reveals a TET2-SNIP1-c-MYC pathway in mediating DNA damage response, thereby connecting epigenetic control to maintenance of genome stability.

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