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

Longfu Xu, Shikai Jin, Mia Urem, Seung-Joo Lee, Meindert H. Lamers, Xun Chen, Peter G. Wolynes () and Gijs J. L. Wuite ()
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Longfu Xu: De Boelelaan 1081
Shikai Jin: 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
Gijs J. L. Wuite: De Boelelaan 1081

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

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62531-1

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