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SUMOylation at K707 of DGCR8 controls direct function of primary microRNA

Changhong Zhu1, Cheng Chen1, Jian Huang1

  • 1Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.

Nucleic Acids Research
|July 24, 2015
PubMed

Insights

SUMOylation of DGCR8 protein enhances its stability and influences its interaction with pri-miRNAs. This modification regulates pri-miRNA direct functions in gene silencing, impacting tumorigenesis and cell migration.

Area of Science:

  • Molecular Biology
  • Gene Regulation
  • Biochemistry

Background:

  • DGCR8 (DiGeorge syndrome critical region gene 8) is crucial for microRNA (miRNA) biogenesis, processing primary miRNA (pri-miRNA) to precursor miRNA (pre-miRNA) in the nucleus.
  • The Microprocessor complex, comprising DGCR8 and Drosha, initiates miRNA processing.
  • Direct roles of pri-/pre-miRNAs in gene expression regulation are suggested, but the fine-tuning mechanisms remain elusive.

Purpose of the Study:

  • To investigate post-translational modifications of DGCR8 and their impact on its function.
  • To elucidate the role of SUMOylation in DGCR8 stability and pri-miRNA interaction.
  • To understand how DGCR8 modification influences pri-miRNA-mediated gene silencing and its implications in diseases like cancer.

Main Methods:

  • Identifying SUMOylation sites on DGCR8 using biochemical assays.
  • Analyzing the effect of SUMOylation on DGCR8 stability and interaction with Drosha and pri-miRNAs.
  • Assessing the impact of DGCR8 SUMOylation on pri-miRNA direct functions and target mRNA repression.
  • Investigating the role of DGCR8 SUMOylation in tumorigenesis and cell migration models.

Main Results:

  • DGCR8 is SUMOylated by SUMO1 at lysine 707 (K707), a modification promoted by ERK-activated phosphorylation.
  • SUMOylation enhances DGCR8 protein stability by inhibiting ubiquitin-proteasome degradation.
  • SUMOylation does not affect DGCR8-Drosha association or Microprocessor complex activity but alters DGCR8 affinity for pri-miRNAs.
  • Altered DGCR8-pri-miRNA interaction influences pri-miRNA-mediated target mRNA recognition and repression, impacting tumorigenesis and cell migration.

Conclusions:

  • SUMOylation of DGCR8 is a novel regulatory mechanism controlling its stability and function.
  • This modification fine-tunes the direct roles of pri-miRNAs in gene silencing by modulating DGCR8's affinity for pri-miRNAs.
  • DGCR8 SUMOylation offers new insights into gene silencing pathways and their links to cancer biology.

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