Oligomerisation of Ku from Mycobacterium tuberculosis promotes DNA synapsis

Sayma Zahid, Sonia Baconnais, Henrietta Smith, Saseela Atwal, Lucy Bates, Harriet Read, Ankita Chadda, Florian Morati, Tom Bedwell, Emil G. P. Stender, Joanne Walter, Steven W. Hardwick, Fredrik Westerlund, Eric Galburt, Eric Le Cam, Alice Pyne, Galina V. Mukamolova and Amanda K. Chaplin ()
Additional contact information
Sayma Zahid: University of Leicester, Leicester Institute for Structural and Chemical Biology, Department of Molecular and Cell Biology
Sonia Baconnais: Gustave Roussy, Genome Integrity and Cancers UMR 9019 CNRS, Université Paris-Saclay
Henrietta Smith: University of Sheffield, School of Chemical, Materials and Biological Engineering
Saseela Atwal: University of Leicester, Leicester Institute for Structural and Chemical Biology, Department of Molecular and Cell Biology
Lucy Bates: University of Leicester, Leicester Tuberculosis Research Group, Department of Respiratory Sciences
Harriet Read: University of Sheffield, School of Chemical, Materials and Biological Engineering
Ankita Chadda: 660 South Euclid Avenue, Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine
Florian Morati: Chalmers University of Technology, Division of Chemical Biology, Department of Life Sciences
Tom Bedwell: 1st, Fida Biosystems Aps, Generatorvej 6
Emil G. P. Stender: 1st, Fida Biosystems Aps, Generatorvej 6
Joanne Walter: 1st, Fida Biosystems Aps, Generatorvej 6
Steven W. Hardwick: Tennis Court Road, Department of Biochemistry, University of Cambridge; Sanger Building
Fredrik Westerlund: Chalmers University of Technology, Division of Chemical Biology, Department of Life Sciences
Eric Galburt: 660 South Euclid Avenue, Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine
Eric Le Cam: Gustave Roussy, Genome Integrity and Cancers UMR 9019 CNRS, Université Paris-Saclay
Alice Pyne: University of Sheffield, School of Chemical, Materials and Biological Engineering
Galina V. Mukamolova: University of Leicester, Leicester Tuberculosis Research Group, Department of Respiratory Sciences
Amanda K. Chaplin: University of Leicester, Leicester Institute for Structural and Chemical Biology, Department of Molecular and Cell Biology

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is estimated to infect nearly one-quarter of the global population. A key factor in its resilience and persistence is its robust DNA repair capacity. Non-homologous end joining (NHEJ) is the primary pathway for repairing DNA double-strand breaks (DSBs) in many organisms, including Mtb, where it is mediated by the Ku protein and the multifunctional LigD enzyme. In this study, we demonstrate that Ku is essential for mycobacterial survival under DNA-damaging conditions. Using cryogenic electron microscopy (cryo-EM), we solved high-resolution structures of both the apo and DNA-bound forms of the Ku-Mtb homodimer. Our structural and biophysical analyses reveal that Ku forms an extended proteo-filament upon binding DNA. We identify critical residues involved in filament formation and DNA synapsis and show that their mutation severely impairs bacterial viability. Furthermore, we propose a model in which the C-terminus of Ku regulates DNA binding and loading and facilitates subsequent recruitment of LigD. These findings provide unique insights into bacterial DNA repair and guide future therapeutics.

Date: 2025
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DOI: 10.1038/s41467-025-65609-y

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