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Structural basis for recognition of 5 '-phosphotyrosine adducts by tdp2

Academic Article
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Overview

authors

  • Shi, K.
  • Kurahashi, K.
  • Gao, R.
  • Tsutakawa, S. E.
  • Tainer, John
  • Pommier, Y.
  • Aihara, H.

publication date

  • December 2012

journal

  • Nature Structural & Molecular Biology  Journal

abstract

  • The DNA-repair enzyme Tdp2 resolves 5'-phosphotyrosyl DNA adducts and mediates resistance to anticancer drugs that target covalent topoisomerase-DNA complexes. Tdp2 also participates in key signaling pathways during development and tumorigenesis and cleaves a protein-RNA linkage during picornavirus replication. The crystal structure of zebrafish Tdp2 bound to DNA reveals a deep, narrow basic groove that selectively accommodates the 5' end of single-stranded DNA in a stretched conformation. The crystal structure of the full-length Caenorhabditis elegans Tdp2 shows that this groove can also accommodate an acidic peptide stretch in vitro, with glutamate and aspartate side chains occupying the DNA backbone phosphate-binding sites. This extensive molecular mimicry suggests a potential mechanism for autoregulation and interaction of Tdp2 with phosphorylated proteins in signaling. Our study provides a framework to interrogate functions of Tdp2 and develop inhibitors for chemotherapeutic and antiviral applications.

subject areas

  • Animals
  • Humans
  • Models, Molecular
  • Nuclear Proteins
  • Phosphotyrosine
  • Signal Transduction
  • Transcription Factors
  • Zebrafish
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Identity

PubMed Central ID

  • PMC3515695

International Standard Serial Number (ISSN)

  • 1545-9993

Digital Object Identifier (DOI)

  • 10.1038/nsmb.2423

PubMed ID

  • 23104058
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Additional Document Info

start page

  • 1372

end page

  • 7

volume

  • 19

issue

  • 12

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