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Title: Mechanism of repair of 5'-topoisomerase II-DNA adducts by mammalian tyrosyl-DNA phosphodiesterase 2

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.

Authors:
; ; ; ; ;  [1];  [2];  [2]
  1. NIH
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
OTHERNIH
OSTI Identifier:
1057304
Resource Type:
Journal Article
Journal Name:
Nature Structural & Molecular Biology
Additional Journal Information:
Journal Volume: 19; Journal Issue: 12; Journal ID: ISSN 1545-9993
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Schellenberg, Matthew J, Appel, C Denise, Adhikari, Sanjay, Robertson, Patrick D, Ramsden, Dale A, Williams, R Scott, Georgetown), and UNC). Mechanism of repair of 5'-topoisomerase II-DNA adducts by mammalian tyrosyl-DNA phosphodiesterase 2. United States: N. p., 2012. Web. doi:10.1038/nsmb.2418.
Schellenberg, Matthew J, Appel, C Denise, Adhikari, Sanjay, Robertson, Patrick D, Ramsden, Dale A, Williams, R Scott, Georgetown), & UNC). Mechanism of repair of 5'-topoisomerase II-DNA adducts by mammalian tyrosyl-DNA phosphodiesterase 2. United States. doi:10.1038/nsmb.2418.
Schellenberg, Matthew J, Appel, C Denise, Adhikari, Sanjay, Robertson, Patrick D, Ramsden, Dale A, Williams, R Scott, Georgetown), and UNC). Sun . "Mechanism of repair of 5'-topoisomerase II-DNA adducts by mammalian tyrosyl-DNA phosphodiesterase 2". United States. doi:10.1038/nsmb.2418.
@article{osti_1057304,
title = {Mechanism of repair of 5'-topoisomerase II-DNA adducts by mammalian tyrosyl-DNA phosphodiesterase 2},
author = {Schellenberg, Matthew J and Appel, C Denise and Adhikari, Sanjay and Robertson, Patrick D and Ramsden, Dale A and Williams, R Scott and Georgetown) and UNC)},
abstractNote = {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.},
doi = {10.1038/nsmb.2418},
journal = {Nature Structural & Molecular Biology},
issn = {1545-9993},
number = 12,
volume = 19,
place = {United States},
year = {2012},
month = {10}
}