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miR-19, a component of the oncogenic miR-17∼92 cluster, targets the DNA-end resection factor CtIP

D Hühn1, A N Kousholt2, C S Sørensen2

  • 1Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.

Oncogene
|October 14, 2014
PubMed

Insights

MicroRNA-19 (miR-19) promotes cancer by downregulating CtIP, a protein crucial for repairing DNA double-strand breaks (DSBs). This impairs homologous recombination (HR) repair, leading to DNA damage hypersensitivity and genomic instability.

Area of Science:

  • Molecular Biology
  • Oncology
  • Genetics

Background:

  • The miR-17∼92 cluster, known as oncomiR-1, contains microRNA-19 (miR-19) as a key oncogenic component frequently amplified in tumors.
  • The tumor-promoting mechanisms of miR-19 are not fully understood, particularly its gene targets and affected pathways.
  • CtIP (RBBP8) is a tumor suppressor involved in DNA double-strand break (DSB) repair via homologous recombination (HR).

Purpose of the Study:

  • To investigate the gene targets and molecular mechanisms underlying the oncogenic activity of miR-19.
  • To determine if miR-19 directly targets CtIP and affects its function in DNA repair.

Main Methods:

  • Bioinformatic analysis to identify potential miR-19 binding sites on CtIP mRNA.
  • Western blotting and qRT-PCR to assess CtIP expression levels after miR-19 manipulation.
  • DNA combing and gamma-H2AX foci assays to evaluate DNA-end resection and DSB repair efficiency.
  • Cellular assays to assess DNA damage hypersensitivity and homologous recombination (HR) levels.

Main Results:

  • miR-19 directly downregulates CtIP expression by binding to conserved sites in its 3'-untranslated region.
  • CtIP expression is repressed by miR-19 under genotoxic stress in a p53-dependent manner.
  • miR-19 overexpression impairs CtIP-mediated DNA-end resection, reducing HR and causing DNA damage hypersensitivity.

Conclusions:

  • miR-19 acts as an oncoprotein by inhibiting CtIP-dependent DNA repair pathways.
  • Downregulation of CtIP by miR-19 disrupts faithful DSB repair, contributing to genome instability and tumor progression.
  • These findings elucidate a novel mechanism for the oncogenic role of the miR-17∼92 cluster.

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