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

Marianna Genta, Giulia Ferrara, Riccardo Capelli, Diego Rondelli, Sarah Sertic, Martino Bolognesi, Menico Rizzi, Franca Rossi, David Jeruzalmi, Antonio Chaves-Sanjuan () and Riccardo Miggiano ()
Additional contact information
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
Menico Rizzi: Via Bovio 6
Franca Rossi: Via Bovio 6
David Jeruzalmi: The City College of New York
Antonio Chaves-Sanjuan: University of Milan
Riccardo Miggiano: Via Bovio 6

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58670-0

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