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BRCA1 levels and DNA-damage response are controlled by the competitive binding of circHIPK3 or FMRP to the BRCA1 mRNA

Chiara Grelloni1, Raffaele Garraffo1, Adriano Setti1

  • 1Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, 00185 Rome, Italy.

Molecular Cell
|October 10, 2024
PubMed

Insights

Circular RNAs (circRNAs) regulate cancer by interacting with BRCA1 mRNA. This interaction, mediated by FMRP protein, impacts DNA damage response and cancer cell sensitivity to treatments.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • RNA Biology

Background:

  • Circular RNAs (circRNAs) are prevalent in eukaryotes and implicated in various diseases, including cancer.
  • While known as miRNA sponges or protein sponges, their role in mRNA fate regulation is less understood.

Purpose of the Study:

  • To investigate the function of circHIPK3 in regulating mRNA fate through direct circRNA-mRNA interactions.
  • To elucidate the mechanism by which circHIPK3 influences BRCA1 mRNA translation and its impact on cancer cells.

Main Methods:

  • Investigated in vivo interaction between circHIPK3 and BRCA1 mRNA in human cancer cells.
  • Identified the fragile-X mental retardation 1 protein (FMRP) as a BRCA1 translational repressor.
  • Utilized circRNA depletion, disruption of circRNA-mRNA interaction, and locked nucleic acid (LNA) to modulate protein levels and assess cellular response.

Main Results:

  • circHIPK3 directly interacts with BRCA1 mRNA, enhancing its translation by competing for FMRP binding.
  • Depletion of circHIPK3 or disruption of the interaction reduces BRCA1 protein levels, leading to increased DNA damage.
  • Cancer cells with disrupted circHIPK3-BRCA1 interaction show increased sensitivity to DNA-damaging agents and synthetic lethality.

Conclusions:

  • circHIPK3 acts as a positive regulator of BRCA1 translation through direct interaction with BRCA1 mRNA.
  • This circRNA-mRNA interaction is crucial for regulating the DNA damage response in cancer cells.
  • Targeting this interaction offers potential therapeutic strategies for cancer treatment, particularly in combination with DNA-damaging agents.
Keywords:
BRCA1DNA-damage responseFMRPRNA-RNA interactionanti-cancer treatmentscircRNAstranslational regulation

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