Mechanism of repair of 5′-topoisomerase II-DNA adducts by mammalian tyrosyl-DNA phosphodiesterase 2

Matthew J. Schellenberg, C. Denise Appel, Sanjay Adhikari, Patrick D. Robertson, Dale A. Ramsden, R. Scott Williams

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

The topoisomerase II (topo II) DNA incision-and-ligation cycle can be poisoned (for example following treatment with cancer chemotherapeutics) to generate cytotoxic DNA double-strand breaks (DSBs) with topo II covalently conjugated to DNA. Tyrosyl-DNA phosphodiesterase 2 (Tdp2) protects genomic integrity by reversing 5′-phosphotyrosyl-linked topo II-DNA adducts. Here, X-ray structures of mouse Tdp2-DNA complexes reveal that Tdp2 β-2-helix-β DNA damage-binding 'grasp', helical 'cap' and DNA lesion-binding elements fuse to form an elongated protein-DNA conjugate substrate-interaction groove. The Tdp2 DNA-binding surface is highly tailored for engagement of 5′-adducted single-stranded DNA ends and restricts nonspecific endonucleolytic or exonucleolytic processing. Structural, mutational and functional analyses support a single-metal ion catalytic mechanism for the exonuclease-endonuclease-phosphatase (EEP) nuclease superfamily and establish a molecular framework for targeted small-molecule blockade of Tdp2-mediated resistance to anticancer topoisomerase drugs.

Original languageEnglish (US)
Pages (from-to)1363-1371
Number of pages9
JournalNature Structural and Molecular Biology
Volume19
Issue number12
DOIs
StatePublished - Dec 2012

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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