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Updated: Nov 18, 2025
Assessment of Global DNA Double-Strand End Resection using BrdU-DNA Labeling coupled with Cell Cycle Discrimination Imaging
Published on: April 28, 2021
Inducing DNA damage through R-loops to kill cancer cells
Fred C Lam1,2,3,4, Yi Wen Kong2,3,4, Michael B Yaffe2,3,4,5
1Division of Neurosurgery, Hamilton General Hospital, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada.
Abstract:
R-loops are intermediate structures of transcription that can accumulate when transcriptional elongation is blocked by inhibiting BRD4. In normal cells, R-loop persistence suppresses firing of adjacent replication origins. This control is lost in a subset of cancer cells, where BRD4 inhibition results in R-loop accumulation, leading to transcription-replication collisions and DNA double-strand breaks during S-phase, followed by cell death. This finding sheds new light on the mechanisms by which BRD4 inhibitors function as cancer therapies, and indicates that targeting other cellular events to cause R-loop accumulation may be useful for cancer treatment.
Insights
Bromodomain 4 (BRD4) inhibition causes R-loop accumulation in cancer cells, leading to DNA damage and cell death. This reveals a new mechanism for BRD4 inhibitors in cancer therapy.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- R-loops are nucleic acid structures formed during transcription.
- BRD4 (Bromodomain 4) plays a role in transcriptional regulation.
- R-loop accumulation can occur when transcriptional elongation is inhibited.
Purpose of the Study:
- To investigate the consequences of BRD4 inhibition on R-loop formation.
- To understand the role of R-loops in cancer cell death upon BRD4 inhibition.
- To explore novel therapeutic strategies targeting R-loop accumulation in cancer.
Main Methods:
- Inhibition of BRD4 in cancer cell models.
- Analysis of R-loop accumulation and its effects on DNA.
- Assessment of cell death pathways following R-loop persistence.
Main Results:
- BRD4 inhibition leads to significant R-loop accumulation in a subset of cancer cells.
- Accumulated R-loops cause transcription-replication collisions during S-phase.
- These collisions result in DNA double-strand breaks and subsequent cancer cell death.
Conclusions:
- BRD4 inhibitors exert their anti-cancer effects, in part, by inducing R-loop accumulation and DNA damage.
- The loss of R-loop-mediated control of replication origins in cancer cells is critical.
- Targeting cellular events that promote R-loop accumulation presents a potential new avenue for cancer therapy.
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