Torsion is a dynamic regulator of DNA replication stalling and reactivation

DNA's helical structure necessitates replisome rotation relative to DNA during replication, creating inevitable topological challenges. How replication generates and overcomes torsional stress remains unclear. Here, we developed a high-resolution, label-free, real-time assay to track DNA rotation by T7 replisome and its slowing under torsional stress. While helicase or DNA polymerase (DNAP) alone is a weak rotary motor, together they form the most powerful DNA rotary motor yet studied, generating ~22 pN·nm torque before stalling, twice that of E. coli RNA polymerase. Upon stalling, helicase-DNAP interactions stabilize the fork; without them, regression can extend hundreds of base pairs. Prolonged stalling inactivates the replisome, but excess DNAP, aided by interactions with helicase, promotes restart. Gyrase supports steady replication and enables timely restart of stalled forks. These findings demonstrate that helicase-DNAP synergy is essential for maintaining fork integrity under torsion, and that torsion is a key regulator of replication stalling and reactivation.

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Publication Details

Journal
Nature Communications
Published
2025-11-26
DOI
https://doi.org/10.1038/s41467-025-65567-5
Primary Topic
DNA Repair Mechanisms
Type
article
Field-Weighted Citation Impact
0.00

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article

Torsion is a dynamic regulator of DNA replication stalling and reactivation

Fahad Rashid, Michelle D. Wang, James T. Inman, Xiang Gao et al.
Nature Communications
DNA Repair Mechanisms
article

Torsion is a dynamic regulator of DNA replication stalling and reactivation

Fahad Rashid, Michelle D. Wang, James T. Inman, Xiang Gao, Smita S. Patel, Xiaomeng Jia, James M. Berger, Anupam Singh, Yifeng Hong, Shuming Zhang
article en

Abstract

DNA's helical structure necessitates replisome rotation relative to DNA during replication, creating inevitable topological challenges. How replication generates and overcomes torsional stress remains unclear. Here, we developed a high-resolution, label-free, real-time assay to track DNA rotation by T7 replisome and its slowing under torsional stress. While helicase or DNA polymerase (DNAP) alone is a weak rotary motor, together they form the most powerful DNA rotary motor yet studied, generating ~22 pN·nm torque before stalling, twice that of E. coli RNA polymerase. Upon stalling, helicase-DNAP interactions stabilize the fork; without them, regression can extend hundreds of base pairs. Prolonged stalling inactivates the replisome, but excess DNAP, aided by interactions with helicase, promotes restart. Gyrase supports steady replication and enables timely restart of stalled forks. These findings demonstrate that helicase-DNAP synergy is essential for maintaining fork integrity under torsion, and that torsion is a key regulator of replication stalling and reactivation.

Nature CommunicationsVol. 16(1)
Rutgers, The State University of New Jersey (US), Howard Hughes Medical Institute (US), Johns Hopkins University (US), Cornell University (US), Johns Hopkins Medicine (US), Johnson University (US)
National Science Foundation, National Institutes of Health
Openalex Percentile: Top 67%
DNA Repair Mechanisms
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