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Updated: Aug 18, 2025

Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
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RAD18 opposes transcription-associated genome instability through FANCD2 recruitment.

James P Wells1, Emily Yun-Chia Chang1, Leticia Dinatto1,2

  • 1Terry Fox Laboratory, BC Cancer, Vancouver, Canada.

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RAD18 deficiency increases transcription-replication conflicts and DNA:RNA hybrids, leading to genome instability. A RAD18-dependent pathway involving FANCD2 suppresses these R-loops and conflicts during DNA replication.

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Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • DNA replication is crucial for genome stability but is vulnerable to various stressors.
  • Transcription-replication conflicts and DNA:RNA hybrids (R-loops) pose significant threats during replication.
  • RAD18, an E3 ubiquitin ligase for PCNA, plays a role in DNA damage tolerance pathways.

Purpose of the Study:

  • To investigate the role of RAD18 in managing transcription-replication conflicts and R-loops.
  • To elucidate the mechanism by which RAD18 maintains genome stability during replication stress.

Main Methods:

  • Analysis of RAD18 deficient cells.
  • Assessment of transcription-replication conflicts and R-loop accumulation.
  • Investigation of Fanconi Anemia complementation group D2 (FANCD2) recruitment and activation.

Main Results:

  • RAD18 deficient cells exhibit increased transcription-replication conflicts and R-loop accumulation.
  • These cells also show higher levels of DNA double-strand breaks and replication stress.
  • Failure to recruit FANCD2 at R-loop prone sites contributes to these phenotypes.
  • RAD18 activity is critical for FANCD2 activation.

Conclusions:

  • RAD18 is essential for suppressing R-loops and transcription-replication conflicts.
  • A RAD18-dependent pathway involving FANCD2 is crucial for maintaining genome stability during replication.
  • This pathway mitigates replication stress induced by R-loops and conflicts.