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

Science, vol. 388, pp. 1225–1231

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.

Authors 13

1. Koichi Sato corresponding Aachen Department of Human Genetics

   Leiden University Medical Center · University Medical Center Utrecht · Oncode Institute

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands

   Oncode Institute, Hubrecht Institute-KNAW & University Medical Center Utrecht, Utrecht, Netherlands

2. Jing Lyu

   Science for Life Laboratory · Karolinska Institutet · Ming Wai Lau Centre for Reparative Medicine

   Affiliation as printed

   Ming Wai Lau Centre for Reparative Medicine, Stockholm node, Karolinska Institutet, Stockholm, Sweden

   Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

3. Jeroen van den Berg

   University Medical Center Utrecht · Oncode Institute

   Affiliation as printed

   Oncode Institute, Hubrecht Institute-KNAW & University Medical Center Utrecht, Utrecht, Netherlands

4. Victoria M. Cruz Aachen Department of Human Genetics

   Leiden University Medical Center · University Medical Center Utrecht · Oncode Institute

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands

   Oncode Institute, Hubrecht Institute-KNAW & University Medical Center Utrecht, Utrecht, Netherlands

5. Joost Schimmel Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands

6. Clara Esteban-Jurado Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands

7. Jan Dreyer

   University Medical Center Utrecht

   Affiliation as printed

   Hubrecht Institute-KNAW & University Medical Center Utrecht, Utrecht, Netherlands

8. Aiko Hendrikx

   University Medical Center Utrecht · Oncode Institute

   Affiliation as printed

   Oncode Institute, Hubrecht Institute-KNAW & University Medical Center Utrecht, Utrecht, Netherlands

9. Francesca Mattiroli

   University Medical Center Utrecht

   Affiliation as printed

   Hubrecht Institute-KNAW & University Medical Center Utrecht, Utrecht, Netherlands

10. Alexander van Oudenaarden

    University Medical Center Utrecht · Oncode Institute

    Affiliation as printed

    Oncode Institute, Hubrecht Institute-KNAW & University Medical Center Utrecht, Utrecht, Netherlands

11. Marcel Tijsterman Aachen Department of Human Genetics Institute of Biology Leiden

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands

    Institute of Biology Leiden, Leiden University, Leiden, Netherlands

12. Simon J. Elsässer

    Science for Life Laboratory · Karolinska Institutet · Ming Wai Lau Centre for Reparative Medicine

    Affiliation as printed

    Ming Wai Lau Centre for Reparative Medicine, Stockholm node, Karolinska Institutet, Stockholm, Sweden

    Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

13. Puck Knipscheer corresponding Aachen Department of Human Genetics

    Leiden University Medical Center · University Medical Center Utrecht · Oncode Institute

    Affiliation as printed

    Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands

    Oncode Institute, Hubrecht Institute-KNAW & University Medical Center Utrecht, Utrecht, Netherlands