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

Jihee Hwang, Chun-Ying Lee, Sumitabha Brahmachari, Shubham Tripathi, Tapas Paul, Huijin Lee, Alanna Craig, Taekjip Ha and Sua Myong ()
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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
Sua Myong: Boston Children’s Hospital and Harvard Medical School

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58479-x

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