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Excessive reactive oxygen species induce transcription-dependent replication stress
Martin Andrs1,2, Henriette Stoy2, Barbora Boleslavska1,3
1Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
Nature Communications
|March 30, 2023
Summary
Oxidative stress triggers replication fork reversal via R-loops, impacting genomic stability. This process, linked to transcription, contributes to cancer-associated alterations.
Area of Science:
- Molecular Biology
- Genomics
- Cancer Research
Background:
- Reactive oxygen species (ROS) impair DNA replication by destabilizing the TIMELESS-TIPIN complex.
- Understanding replication fork dynamics under stress is crucial for cancer research.
Purpose of the Study:
- To investigate the role of ROS in replication fork reversal.
- To elucidate the mechanisms linking oxidative stress, transcription, and DNA damage.
Main Methods:
- Exposure of human cells to hydroxyurea (HU) to induce ROS.
- Analysis of replication fork dynamics, transcription, and R-loop formation.
- TIMELESS depletion and aphidicolin treatment to modulate replication stress.
Main Results:
- ROS promote replication fork reversal dependent on active transcription and R-loops.
- Global replication slowdown, not just deoxynucleotide depletion, increases R-loop-dependent stalling.
- Persistent replication arrest leads to R-loop-independent DNA breakage.
Conclusions:
- Oxidative stress and transcription-replication conflicts are linked.
- This interplay contributes to genomic alterations found in human cancers.
- Findings provide insights into cancer development and potential therapeutic targets.
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