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DNA polymerase actively and sequentially displaces single-stranded DNA-binding proteins

Author

Listed:
  • Longfu Xu

    (De Boelelaan 1081)

  • Shikai Jin

    (Rice University
    Rice University)

  • Mia Urem

    (Leiden University Medical Center)

  • Seung-Joo Lee

    (Harvard Medical School)

  • Meindert H. Lamers

    (Leiden University Medical Center (LUMC))

  • Xun Chen

    (Nanjing Medical University)

  • Peter G. Wolynes

    (Rice University
    Rice University
    Rice University)

  • Gijs J. L. Wuite

    (De Boelelaan 1081)

Abstract

Single-stranded DNA-binding proteins (SSBs) protect transiently exposed ssDNA, yet how DNA polymerase (DNAp) displaces them during replication remains unclear. Using single-molecule force spectroscopy, dual-color imaging, and molecular dynamics simulations on bacteriophage T7 DNAp and SSB, we investigated molecular mechanisms underlying SSB displacement. T7 SSB modulates replication in a force-dependent manner: enhancing it at low tension by preventing secondary structures while impeding it at high tension. Dual-color imaging shows SSBs remain stationary as DNAp advances, supporting a sequential displacement model. Molecular dynamics suggests that DNAp actively lowers the SSB dissociation energy barrier through interactions mediated by the SSB C-terminal tail. FRET confirms close protein proximity during encounters. Optimal replication requires SSB saturation of ssDNA, establishing a delicate balance between protection and efficiency. This spatiotemporal coordination between DNAp and SSB is critical for resolving molecular collisions and may represent a general mechanism for resolving molecular collisions, ensuring both processivity and genomic integrity.

Suggested Citation

  • Longfu Xu & Shikai Jin & Mia Urem & Seung-Joo Lee & Meindert H. Lamers & Xun Chen & Peter G. Wolynes & Gijs J. L. Wuite, 2025. "DNA polymerase actively and sequentially displaces single-stranded DNA-binding proteins," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62531-1
    DOI: 10.1038/s41467-025-62531-1
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