RNA transcripts regulate G-quadruplex landscapes through G-loop formation

G-quadruplexes (G4s) are prevalent DNA structures that regulate transcription but also threaten genome stability. How G4 dynamics are controlled remains poorly understood. Here, we report that RNA transcripts govern G4 landscapes through coordinated G-loop assembly and disassembly. G-loop assembly involves activation of the ATM and ATR kinases, followed by homology-directed invasion of RNA opposite the G4 strand mediated by BRCA2 and RAD51. Disassembly of the G-loop resolves the G4 structure through DHX36-FANCJ-mediated G4 unwinding, which triggers nucleolytic incision and subsequent hybrid strand renewal by DNA synthesis. Inhibition of G-loop disassembly causes global G4 and R-loop accumulation, leading to transcriptome dysregulation, replication stress, and genome instability. These findings establish an intricate G-loop assembly-disassembly mechanism that controls G4 landscapes and is essential for cellular homeostasis and survival.

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Publication Details

Journal
Science
Published
2025-06-12
DOI
https://doi.org/10.1126/science.adr0493
Citations
17
Primary Topic
DNA and Nucleic Acid Chemistry
Type
article
Field-Weighted Citation Impact
13.70
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RNA transcripts regulate G-quadruplex landscapes through G-loop formation

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article en
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Abstract

G-quadruplexes (G4s) are prevalent DNA structures that regulate transcription but also threaten genome stability. How G4 dynamics are controlled remains poorly understood. Here, we report that RNA transcripts govern G4 landscapes through coordinated G-loop assembly and disassembly. G-loop assembly involves activation of the ATM and ATR kinases, followed by homology-directed invasion of RNA opposite the G4 strand mediated by BRCA2 and RAD51. Disassembly of the G-loop resolves the G4 structure through DHX36-FANCJ-mediated G4 unwinding, which triggers nucleolytic incision and subsequent hybrid strand renewal by DNA synthesis. Inhibition of G-loop disassembly causes global G4 and R-loop accumulation, leading to transcriptome dysregulation, replication stress, and genome instability. These findings establish an intricate G-loop assembly-disassembly mechanism that controls G4 landscapes and is essential for cellular homeostasis and survival.

ScienceVol. 388(6752)
Leiden University (NL), Leiden University Medical Center (NL), Science for Life Laboratory (SE), Karolinska Institutet (SE), Oncode Institute (NL), Hubrecht Institute for Developmental Biology and Stem Cell Research (NL)
Life in Land
Openalex Percentile: Top 1%
DNA and Nucleic Acid Chemistry
13.70
DOIOpen Access PDFOpenAlex
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