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DNA supercoiling-mediated G4/R-loop formation tunes transcription by controlling the access of RNA polymerase

Author

Listed:
  • Jihee Hwang

    (Boston Children’s Hospital and Harvard Medical School)

  • Chun-Ying Lee

    (Boston Children’s Hospital and Harvard Medical School)

  • Sumitabha Brahmachari

    (Rice University)

  • Shubham Tripathi

    (Yale School of Medicine)

  • Tapas Paul

    (Boston Children’s Hospital and Harvard Medical School)

  • Huijin Lee

    (Johns Hopkins University School of Medicine)

  • Alanna Craig

    (Johns Hopkins University)

  • Taekjip Ha

    (Boston Children’s Hospital and Harvard Medical School
    Johns Hopkins University School of Medicine
    Johns Hopkins University
    Johns Hopkins University)

  • Sua Myong

    (Boston Children’s Hospital and Harvard Medical School
    Johns Hopkins University School of Medicine
    Johns Hopkins University)

Abstract

RNA polymerase (RNAP) is a processive motor that modulates DNA supercoiling and reshapes DNA structures. The feedback loop between the DNA topology and transcription remains elusive. Here, we investigate the impact of potential G-quadruplex forming sequences (PQS) on transcription in response to DNA supercoiling. We find that supercoiled DNA increases transcription frequency 10-fold higher than relaxed DNA, which lead to an abrupt formation of G-quadruplex (G4) and R-loop structures. Moreover, the stable R-loop relieves topological strain, facilitated by G4 formation. The cooperative formation of G4/R-loop effectively alters the DNA topology around the promoter and suppresses transcriptional activity by impeding RNAP loading. These findings highlight negative supercoiling as a built-in spring that triggers a transcriptional burst followed by a rapid suppression upon G4/R-loop formation. This study sheds light on the intricate interplay between DNA topology and structural change in transcriptional regulation, with implications for understanding gene expression dynamics.

Suggested Citation

  • Jihee Hwang & Chun-Ying Lee & Sumitabha Brahmachari & Shubham Tripathi & Tapas Paul & Huijin Lee & Alanna Craig & Taekjip Ha & Sua Myong, 2025. "DNA supercoiling-mediated G4/R-loop formation tunes transcription by controlling the access of RNA polymerase," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58479-x
    DOI: 10.1038/s41467-025-58479-x
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    References listed on IDEAS

    as
    1. Chun-Ying Lee & Christina McNerney & Kevin Ma & Walter Zhao & Ashley Wang & Sua Myong, 2020. "R-loop induced G-quadruplex in non-template promotes transcription by successive R-loop formation," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    2. Chengjin Zhu & Xieyang Guo & Philippe Dumas & Maria Takacs & Mo’men Abdelkareem & Arnaud Vanden Broeck & Charlotte Saint-André & Gabor Papai & Corinne Crucifix & Julio Ortiz & Albert Weixlbaumer, 2022. "Transcription factors modulate RNA polymerase conformational equilibrium," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    Full references (including those not matched with items on IDEAS)

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