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Thrap3 promotes R-loop resolution via interaction with methylated DDX5.

Hyun Je Kang1, Hye-Jin Eom1, Hongtae Kim1

  • 1Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Korea.

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Thyroid hormone receptor-associated protein 3 (Thrap3) prevents R-loop accumulation and DNA damage in cancer cells. This protein interacts with DDX5 and XRN2 to resolve R-loops, promoting cell survival.

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Area of Science:

  • Molecular biology
  • Genetics
  • Cancer research

Background:

  • Transcription-replication conflicts cause DNA damage and genomic instability, linked to diseases.
  • R-loops, RNA-DNA hybrids, are a major source of these conflicts, but their biology is not fully understood.

Purpose of the Study:

  • To investigate the role of thyroid hormone receptor-associated protein 3 (Thrap3) in regulating R-loop resolution and its impact on genome stability.

Main Methods:

  • Investigated Thrap3 interactions with DEAD-box helicase 5 (DDX5) and 5'-3' exoribonuclease 2 (XRN2) in cancer cells.
  • Analyzed the effect of Thrap3 and DDX5 methylation on R-loop formation and DNA damage.

Main Results:

  • Thrap3 interacts with DDX5 at R-loops, and DDX5 methylation is crucial for this interaction.
  • The Thrap3-DDX5 complex recruits XRN2 to R-loops, promoting their resolution.
  • Loss of Thrap3 leads to increased R-loop accumulation and DNA damage.

Conclusions:

  • Thrap3 plays a critical role in R-loop resolution, preventing R-loop accumulation and associated DNA damage.
  • The Thrap3-DDX5-XRN2 axis is essential for maintaining genome stability in cancer cells.
  • Thrap3 promotes cancer cell survival by mitigating R-loop-induced genotoxicity.