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Studying RNA Interactors of Protein Kinase RNA-Activated during the Mammalian Cell Cycle
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Studying RNA Interactors of Protein Kinase RNA-Activated during the Mammalian Cell Cycle

Published on: March 5, 2019

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The kinase ABL phosphorylates the microprocessor subunit DGCR8 to stimulate primary microRNA processing in response

Chi-Chiang Tu1, Yan Zhong2, Louis Nguyen2

  • 1Moores Cancer Center and Division of Hematology-Oncology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0644, USA. Institute of Biomedical Sciences, Academia Sinica, Taipei 11529 Taiwan.

Science Signaling
|July 2, 2015
PubMed

Insights

The DNA damage response involves ABL tyrosine kinase phosphorylating DGCR8, a protein crucial for microRNA (miRNA) production. This phosphorylation selectively enhances specific miRNA processing, like miR-34c, aiding cellular repair mechanisms.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • The DNA damage response network coordinates cellular processes including repair, cell cycle control, and apoptosis.
  • MicroRNA (miRNA) biogenesis is a key component of this network, involving the microprocessor complex (Drosha and DGCR8).
  • The precise mechanisms regulating selective miRNA production following DNA damage are not fully understood.

Purpose of the Study:

  • To investigate the role of tyrosine kinase ABL in miRNA biogenesis within the DNA damage response.
  • To elucidate the mechanism by which ABL influences the processing of specific miRNAs, such as the miR-34 family.
  • To determine the functional consequences of ABL-mediated regulation of miRNA processing in cellular responses to DNA damage.

Main Methods:

  • Investigated the phosphorylation of DGCR8 by ABL in response to DNA damage.
  • Utilized RNA cross-linking assays and co-expression studies in HEK293T cells to analyze protein-miRNA interactions and processing.
  • Employed a mouse model with a nuclear import-defective ABL mutant to assess in vivo miRNA expression and apoptosis.

Main Results:

  • ABL directly phosphorylates DGCR8 at Tyr(267), a modification essential for inducing a subset of miRNAs after DNA damage.
  • ABL selectively stimulates the processing of pri-miR-34c, but not pri-miR-34a, via the Drosha/DGCR8 complex, dependent on flanking sequences.
  • Phosphorylation of DGCR8 by ABL inversely correlates with DGCR8 binding to pri-miR-34c, impacting Drosha recruitment and pri-miRNA processing.

Conclusions:

  • ABL-dependent tyrosine phosphorylation of DGCR8 represents a novel regulatory pathway in the DNA damage response.
  • This pathway fine-tunes the production of specific primary miRNAs (pri-miRNAs), influencing cellular outcomes like apoptosis.
  • The findings reveal a mechanism for selective miRNA processing, highlighting the intricate coordination between DNA repair and gene regulation.

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