Essential role of the amino-terminal region of Drosha for the Microprocessor function

Amit Prabhakar1, Song Hu2, Jin Tang2

  • 1Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.

Iscience
|October 9, 2023
PubMed

Insights

The Drosha-NTR is essential for microRNA production and nutrient-dependent control of protein synthesis. Its absence causes global microRNA depletion and unregulated cell growth.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Drosha is a key enzyme in microRNA processing, regulating ribosomal protein gene expression.
  • Mutations in Drosha's amino-terminal region (Drosha-NTR) are linked to hereditary hemorrhagic telangiectasia, but its function is poorly understood.

Purpose of the Study:

  • To investigate the precise function of Drosha-NTR in microRNA biogenesis and cellular regulation.
  • To elucidate the role of Drosha-NTR in nutrient-dependent translational control.

Main Methods:

  • Generated a Drosha mutant lacking the amino-terminal region (ΔN) by deleting exon 5.
  • Assessed pri-miRNA processing, microRNA levels, and protein synthesis in wild-type and ΔN cells.
  • Investigated the role of Argonaute 2 in pri-miR-183/96/182 processing.

Main Results:

  • The Drosha ΔN mutant is deficient in pri-miRNA processing, leading to global microRNA depletion, with an exception for the miR-183/96/182 cluster.
  • Argonaute 2 facilitates the processing of pri-miR-183/96/182 in Drosha ΔN cells.
  • Unlike wild-type Drosha, ΔN is resistant to degradation during serum starvation, causing uncontrolled ribosomal protein biogenesis and protein synthesis, thus preventing growth arrest.

Conclusions:

  • Drosha-NTR is crucial for efficient microRNA production.
  • Drosha-NTR plays a vital role in nutrient-dependent translational control and cell cycle regulation.
  • The findings shed light on the molecular mechanisms underlying vascular disorders associated with Drosha mutations.

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