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Loss of TOP3B leads to increased R-loop formation and genome instability

Tao Zhang1,2, Mathew Wallis3,4, Vida Petrovic5

  • 1Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria 3052, Australia.

Open Biology
|December 5, 2019
PubMed

Insights

Topoisomerase III beta (TOP3B) disruption causes genome instability and DNA damage by increasing R-loop formation. This finding identifies TOP3B as a potential cancer gene involved in renal cancer aetiology.

Area of Science:

  • Genetics
  • Molecular Biology
  • Oncology

Background:

  • Topoisomerase III beta (TOP3B) is a poorly understood protein.
  • Its role in disease, particularly cancer, is largely unknown.
  • R-loops are implicated in various pathologies, including cancer.

Purpose of the Study:

  • To investigate the function and disease relevance of TOP3B.
  • To elucidate the molecular mechanisms underlying TOP3B disruption.
  • To assess TOP3B as a potential cancer gene.

Main Methods:

  • Analysis of a patient with a homozygous TOP3B deletion and bilateral renal cancer.
  • Cellular studies using modelled human cells with TOP3B disruption.
  • Assessment of genome instability, DNA damage, and R-loop formation.

Main Results:

  • TOP3B disruption leads to genome instability, increased DNA damage, and chromosome bridging.
  • The primary molecular defect is a significant increase in R-loop accumulation.
  • TOP3B is essential for preventing excessive R-loop formation.

Conclusions:

  • TOP3B is crucial for maintaining genome stability by regulating R-loop levels.
  • TOP3B is identified as a putative cancer gene.
  • These findings support the role of R-loops in cancer development and highlight TOP3B as a potential therapeutic target.
Keywords:
R-loopTOP3Bgenomic instabilitytopoisomerase

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