Abstract
Natural transformation drives the spread of antibiotic resistance among bacteria. The DNA receptor ComEA is essential for transporting external transforming DNA into the periplasm by an unknown mechanism. Here, single-molecule optical tweezers and electron microscopy approaches show that Geobacillus stearothermophilus ComEA forms dynamic oligomers on DNA that can switch between two conformations depending on local concentration. When ComEA sparsely decorates DNA, it forms bridging oligomers that condense the DNA to generate sub-pN pulling forces. When ComEA more fully decorates DNA, it forms non-bridging oligomers that decondense DNA and cannot generate force. Mutating ComEA to favor either bridging or non-bridging conformations causes transformation deficiency in Bacillus subtilis, meaning condensation and decondensation each play mechanistic roles. Our results show that ComEA reversibly condenses DNA during natural transformation, first producing force to pull DNA into the periplasm and then abating force production to promote transport into the cytoplasm.
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All data supporting the findings in this paper are provided in the main manuscript and its Supplementary files. Source data are provided within the source data file. Source data are provided with this paper.
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Acknowledgements
We thank members of the Mickolajczyk, Neiditch, and Dubnau Labs for useful discussions. We thank Rajesh Patel for his technical knowledge and the RWJMS Core EM facility that he manages. J.S. was supported by Rutgers IRACDA K12 GM093854 from the NIH. Support for this work was provided by the National Institutes of Health through grants R01GM057720 (M.B.N. and D.D.) and R35GM157075 (K.J.M.). Additional support was provided by a Busch Biomedical Grant from the Office for Research at Rutgers (K.J.M.).
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M.B.N., D.D., and K.J.M. conceived of the project. J.S., G.A., and K.J.M. carried out optical tweezer data acquisition and analysis. J.M., H.C., and A.R. carried out fluorescence polarization and electron microscopy experiments. I.A. prepared recombinant protein samples with guidance from M.B. J.H. carried out B. subtilis experiments with guidance from D.D. K.J.M. wrote the paper together with M.B.N. and D.D., and with input from all authors.
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Santiago, J.I., Ahmed, I., Hahn, J. et al. Reversible DNA condensation drives natural transformation. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70559-0
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DOI: https://doi.org/10.1038/s41467-026-70559-0
