SNIP1 Recruits TET2 to Regulate c-MYC Target Genes and Cellular DNA Damage Response
Lei-Lei Chen,
Huai-Peng Lin,
Wen-Jie Zhou,
Chen-Xi He,
Zhi-Yong Zhang,
Zhou-Li Cheng,
Jun-Bin Song,
Peng Liu,
Xin-Yu Chen,
Yu-Kun Xia,
Xiu-Fei Chen,
Ren-Qiang Sun,
Jing-Ye Zhang,
Yi-Ping Sun,
Lei Song,
Bing-Jie Liu,
Rui-Kai Du,
Chen Ding,
Fei Lan,
Sheng-Lin Huang,
Feng Zhou,
Suling Liu,
Yue Xiong,
Dan Ye,
Kun-Liang Guan
Affiliations
Lei-Lei Chen
Huashan Hospital and Key Laboratory of Medical Epigenetics and Metabolism and Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
Huai-Peng Lin
Huashan Hospital and Key Laboratory of Medical Epigenetics and Metabolism and Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Medical College of Xiamen University, Xiamen 361102, China
Wen-Jie Zhou
Huashan Hospital and Key Laboratory of Medical Epigenetics and Metabolism and Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
Chen-Xi He
Huashan Hospital and Key Laboratory of Medical Epigenetics and Metabolism and Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
Zhi-Yong Zhang
Huashan Hospital and Key Laboratory of Medical Epigenetics and Metabolism and Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
Zhou-Li Cheng
Huashan Hospital and Key Laboratory of Medical Epigenetics and Metabolism and Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
Jun-Bin Song
Huashan Hospital and Key Laboratory of Medical Epigenetics and Metabolism and Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
Peng Liu
Huashan Hospital and Key Laboratory of Medical Epigenetics and Metabolism and Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
Xin-Yu Chen
Huashan Hospital and Key Laboratory of Medical Epigenetics and Metabolism and Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
Yu-Kun Xia
Huashan Hospital and Key Laboratory of Medical Epigenetics and Metabolism and Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
Xiu-Fei Chen
Huashan Hospital and Key Laboratory of Medical Epigenetics and Metabolism and Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
Ren-Qiang Sun
Huashan Hospital and Key Laboratory of Medical Epigenetics and Metabolism and Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
Jing-Ye Zhang
Huashan Hospital and Key Laboratory of Medical Epigenetics and Metabolism and Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
Yi-Ping Sun
Huashan Hospital and Key Laboratory of Medical Epigenetics and Metabolism and Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
Lei Song
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, National Center for National Center for Protein Science (The PHOENIX Center), Beijing, China
Bing-Jie Liu
Fudan University Shanghai Cancer Center, Key Laboratory of Breast Cancer in Shanghai, Innovation Center for Cell Signaling Network, Cancer Institutes, Fudan University, Shanghai, China
Rui-Kai Du
Fudan University Shanghai Cancer Center, Key Laboratory of Breast Cancer in Shanghai, Innovation Center for Cell Signaling Network, Cancer Institutes, Fudan University, Shanghai, China
Chen Ding
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, National Center for National Center for Protein Science (The PHOENIX Center), Beijing, China
Fei Lan
Huashan Hospital and Key Laboratory of Medical Epigenetics and Metabolism and Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
Sheng-Lin Huang
Huashan Hospital and Key Laboratory of Medical Epigenetics and Metabolism and Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
Feng Zhou
Huashan Hospital and Key Laboratory of Medical Epigenetics and Metabolism and Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
Suling Liu
Fudan University Shanghai Cancer Center, Key Laboratory of Breast Cancer in Shanghai, Innovation Center for Cell Signaling Network, Cancer Institutes, Fudan University, Shanghai, China
Yue Xiong
Huashan Hospital and Key Laboratory of Medical Epigenetics and Metabolism and Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Corresponding author
Dan Ye
Huashan Hospital and Key Laboratory of Medical Epigenetics and Metabolism and Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China; Corresponding author
Kun-Liang Guan
Huashan Hospital and Key Laboratory of Medical Epigenetics and Metabolism and Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Corresponding author
Summary: 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. : Chen et al. show SNIP1 recruits TET2 to the promoters of c-MYC target genes, including those involved in DNA damage response and cell viability. This study uncovers a mechanism for targeting TET2 to specific promoters through a ternary interaction with a co-activator and sequence-specific DNA-binding factors and also reveals a TET2-SNIP1-c-MYC pathway in mediating DNA damage response, thereby connecting epigenetic control to maintenance of genome stability. Keywords: TET2, SNIP1, c-MYC, DNA demethylation, transcription, DNA damage, cell death
