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Structural basis for DNA 3′-end processing by human tyrosyl-DNA phosphodiesterase 1

Author

Listed:
  • Fiona J. Flett

    (University of Edinburgh)

  • Emilija Ruksenaite

    (University of Edinburgh)

  • Lee A. Armstrong

    (University of Edinburgh)

  • Shipra Bharati

    (University of Edinburgh)

  • Roberta Carloni

    (University of Edinburgh)

  • Elizabeth R. Morris

    (University of Edinburgh)

  • C. Logan Mackay

    (University of Edinburgh)

  • Heidrun Interthal

    (University of Edinburgh)

  • Julia M. Richardson

    (University of Edinburgh)

Abstract

Tyrosyl-DNA phosphodiesterase (Tdp1) is a DNA 3′-end processing enzyme that repairs topoisomerase 1B-induced DNA damage. We use a new tool combining site-specific DNA–protein cross-linking with mass spectrometry to identify Tdp1 interactions with DNA. A conserved phenylalanine (F259) of Tdp1, required for efficient DNA processing in biochemical assays, cross-links to defined positions in DNA substrates. Crystal structures of Tdp1–DNA complexes capture the DNA repair machinery after 3′-end cleavage; these reveal how Tdp1 coordinates the 3′-phosphorylated product of nucleosidase activity and accommodates duplex DNA. A hydrophobic wedge splits the DNA ends, directing the scissile strand through a channel towards the active site. The F259 side-chain stacks against the −3 base pair, delimiting the junction of duplexed and melted DNA, and fixes the scissile strand in the channel. Our results explain why Tdp1 cleavage is non-processive and provide a molecular basis for DNA 3′-end processing by Tdp1.

Suggested Citation

  • Fiona J. Flett & Emilija Ruksenaite & Lee A. Armstrong & Shipra Bharati & Roberta Carloni & Elizabeth R. Morris & C. Logan Mackay & Heidrun Interthal & Julia M. Richardson, 2018. "Structural basis for DNA 3′-end processing by human tyrosyl-DNA phosphodiesterase 1," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02530-z
    DOI: 10.1038/s41467-017-02530-z
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