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Mechanistic understanding of UvrA damage detection and lesion hand-off to UvrB in Nucleotide Excision Repair

Author

Listed:
  • Marianna Genta

    (Via Bovio 6)

  • Giulia Ferrara

    (Via Bovio 6)

  • Riccardo Capelli

    (University of Milan)

  • Diego Rondelli

    (University of Milan)

  • Sarah Sertic

    (University of Milan)

  • Martino Bolognesi

    (University of Milan
    University of Milan)

  • Menico Rizzi

    (Via Bovio 6)

  • Franca Rossi

    (Via Bovio 6)

  • David Jeruzalmi

    (The City College of New York)

  • Antonio Chaves-Sanjuan

    (University of Milan
    University of Milan)

  • Riccardo Miggiano

    (Via Bovio 6)

Abstract

Nucleotide excision repair (NER) represents one of the major molecular machineries that control chromosome stability in all living species. In Eubacteria, the initial stages of the repair process are carried out by the UvrABC excinuclease complex. Despite the wealth of structural data available, some crucial details of the pathway remain elusive. In this study, we present a structural investigation of the Mycobacterium tuberculosis UvrAUvrB complex and of the UvrA dimer, both in complex with damaged DNA. Our analyses yield insights into the DNA binding mode of UvrA, showing an unexplored conformation of Insertion Domains (IDs), underlying the essential role of these domains in DNA coordination. Furthermore, we observe an interplay between the ID and the UvrB Binding Domain (UBD): after the recognition of the damage, the IDs repositions with the concomitant reorganization of UBD, allowing the formation of the complex between UvrA and UvrB. These events are detected along the formation of the uncharacterized UvrA2UvrB1-DNA and the UvrA2UvrB2-DNA complexes which we interpret as hierarchical steps initiating the DNA repair cascade in the NER pathway, resulting in the formation of the pre-incision complex.

Suggested Citation

  • Marianna Genta & Giulia Ferrara & Riccardo Capelli & Diego Rondelli & Sarah Sertic & Martino Bolognesi & Menico Rizzi & Franca Rossi & David Jeruzalmi & Antonio Chaves-Sanjuan & Riccardo Miggiano, 2025. "Mechanistic understanding of UvrA damage detection and lesion hand-off to UvrB in Nucleotide Excision Repair," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58670-0
    DOI: 10.1038/s41467-025-58670-0
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    References listed on IDEAS

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    1. Mathew Stracy & Marcin Jaciuk & Stephan Uphoff & Achillefs N. Kapanidis & Marcin Nowotny & David J. Sherratt & Pawel Zawadzki, 2016. "Single-molecule imaging of UvrA and UvrB recruitment to DNA lesions in living Escherichia coli," Nature Communications, Nature, vol. 7(1), pages 1-9, November.
    2. Christoph J. Wienken & Philipp Baaske & Ulrich Rothbauer & Dieter Braun & Stefan Duhr, 2010. "Protein-binding assays in biological liquids using microscale thermophoresis," Nature Communications, Nature, vol. 1(1), pages 1-7, December.
    3. Harshad Ghodke & Han Ngoc Ho & Antoine M. Oijen, 2020. "Single-molecule live-cell imaging visualizes parallel pathways of prokaryotic nucleotide excision repair," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    4. Xuejing Chen & Yogambigai Velmurugu & Guanqun Zheng & Beomseok Park & Yoonjung Shim & Youngchang Kim & Lili Liu & Bennett Van Houten & Chuan He & Anjum Ansari & Jung-Hyun Min, 2015. "Kinetic gating mechanism of DNA damage recognition by Rad4/XPC," Nature Communications, Nature, vol. 6(1), pages 1-10, May.
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