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

Abstract

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.

Enrichment of Cxcl12 promoter with TET2: A possible link between promoter demethylation and enhanced gene expression in the absence of PARP-1

“…It was found that TET2 interacts with IDAX protein whose CXXC domain binds to unmethylated CpG dinucleotides in the promoter but in a sequence-nonspecific manner [31]. A very recent report described the mechanism for targeting TET2 to specific promoters [36]. It was proposed that transcriptional co-activator SMAD nuclear interacting protein 1 (SNIP1) bridges TET2 to bind to a sequencespecific DNA-binding factor c-MYC, thus facilitating the recruitment of TET2 to regulate c-MYC target genes by promoting DNA demethylation at the promoters [36].…”

“…A very recent report described the mechanism for targeting TET2 to specific promoters [36]. It was proposed that transcriptional co-activator SMAD nuclear interacting protein 1 (SNIP1) bridges TET2 to bind to a sequencespecific DNA-binding factor c-MYC, thus facilitating the recruitment of TET2 to regulate c-MYC target genes by promoting DNA demethylation at the promoters [36]. In addition, it is well established that the posttranslational modification, monoubiquitylation, which is catalyzed by CRL4VprBP E3 ligase, promotes the DNA binding of TET2 by stabilizing the conformation of TET2 complexed with DNA (where the monoubiquitylation site directly contacts the DNA) [32,37].…”

TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells

“…Within Cluster 12, MYC was by far the most abundantly expressed TF in hematopoietic stem cells. It has previously been reported that DNA methylation inhibits MYCN chromatin binding in Tet1-3 triple knockout ES cells (Yin et al 2017), and a recent study has uncovered that TET2 is recruited to MYC binding sites by SNIP1 in cancer cell lines (Chen et al 2018). However, analysis of chromatin accessibility by diffTF at MYC binding sites (predicted individually from all available MYC DNA-binding motifs) did not show a significant difference in wild-type and Tet2 knockout, possibly due to a complex MYC binding pattern at E-boxes throughout the genome.…”

miR-29a-3p directly targets Smad nuclear interacting protein 1 and inhibits the migration and proliferation of cervical cancer HeLa cells

“…Smad nuclear interacting protein 1 (SNIP1), as an evolutionarily conserved nuclear protein, is involved in essential biological processes such as cell proliferation ( Roche et al, 2004 ; Fujii et al, 2006 ), small RNA biogenesis ( Yu et al, 2008 ), DNA damage response ( Chen et al, 2018 ), and several signaling pathways ( Kim et al, 2000 ; Kim et al, 2001 ). In patients with non-small cell lung cancer or tongue squamous cell carcinoma, SNIP1 might be a reliable prognostic indicator ( Liang et al, 2011 ; Jeon et al, 2013 ).…”