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

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SNIP1 Recruits TET2 to Regulate c-MYC Target Genes and Cellular DNA Damage Response.
Cell Reports ( IF 7.5 ) Pub Date : 2018-11-06 , DOI: 10.1016/j.celrep.2018.10.028
Lei-Lei Chen ₁ , Huai-Peng Lin ₂ , Wen-Jie Zhou ₁ , Chen-Xi He ₁ , Zhi-Yong Zhang ₁ , Zhou-Li Cheng ₁ , Jun-Bin Song ₁ , Peng Liu ₁ , Xin-Yu Chen ₁ , Yu-Kun Xia ₁ , Xiu-Fei Chen ₁ , Ren-Qiang Sun ₁ , Jing-Ye Zhang ₁ , Yi-Ping Sun ₁ , Lei Song ₃ , Bing-Jie Liu ₄ , Rui-Kai Du ₄ , Chen Ding ₃ , Fei Lan ₁ , Sheng-Lin Huang ₁ , Feng Zhou ₁ , Suling Liu ₄ , Yue Xiong ₅ , Dan Ye ₆ , Kun-Liang Guan ₇

Affiliation

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.
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.
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.
Fudan University Shanghai Cancer Center, Key Laboratory of Breast Cancer in Shanghai, Innovation Center for Cell Signaling Network, Cancer Institutes, Fudan University, Shanghai, China.
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.
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.
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.

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.

中文翻译：

SNIP1 招募 TET2 来调节 c-MYC 靶基因和细胞 DNA 损伤反应。

TET2 DNA 双加氧酶通过催化 5-甲基胞嘧啶的去甲基化来调节基因表达，从而对基因组进行表观遗传调节。TET2 不包含序列特异性 DNA 结合域，并且它如何被招募到特定基因组位点尚不完全清楚。在这里，我们进行了哺乳动物双杂交筛选，并确定了多个可能与 TET2 相互作用的转录调节因子。SMAD 核相互作用蛋白 1 (SNIP1) 与 TET2 物理相互作用并桥接 TET2 以结合多种转录因子，包括 c-MYC。SNIP1 将 TET2 募集到 c-MYC 靶基因的启动子，包括那些参与 DNA 损伤反应和细胞活力的基因。TET2 保护细胞免受依赖于 SNIP1 的 DNA 损伤诱导的细胞凋亡。我们的观察揭示了通过与共激活剂和许多序列特异性 DNA 结合因子的三元相互作用将 TET2 靶向特定启动子的机制。该研究还揭示了 TET2-SNIP1-c-MYC 通路介导 DNA 损伤反应，从而将表观遗传控制与维持基因组稳定性联系起来。

更新日期：2018-11-07

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