• Thomas S. Dexheimer
  • Shar-yin N. Huang
  • Benu Brata Das
  • Yves Pommier
Part of the Cancer Drug Discovery and Development book series (CDD&D)


The abortive activity of DNA topoisomerase I (Top1) can lead to DNA single-strand breaks with 3′-protein adducts termed Top1-DNA cleavage complexes. Repair of these DNA lesions in a prompt and accurate manner is essential for cell survival. One of the cellular pathways for repairing such DNA lesions involves tyrosyl-DNA phosphodiesterase 1 (Tdp1). Tdp1 hydrolyzes the phosphodiester bond between a tyrosine residue and a terminal 3′-phosphate of DNA, the type of linkage found in Top1-DNA cleavage complexes. A mutation in Tdp1 is found to cause a rare heredity neurodegenerative disease, spinocerebellar ataxia with axonal neuropathy (SCAN1). Efforts to elucidate the mechanism of Tdp1-depedent DNA repair pathway have identified several other proteins, which form a complex response network with Tdp1. Conversely, structural and biochemical studies suggest that Tdp1 can act on a broad spectrum of 3′-phosphodiester linkages, potentially implicating Tdp1 in other DNA repair pathways. In this chapter we summarize the recent advances in research concerning Tdp1, alternative repair pathways for repairing Top1-induced DNA damage, and the rational for targeting Tdp1 as a potential anticancer therapy.


Spinocerebellar Ataxia Phosphodiester Bond Cleavage Complex Base Excision Repair Pathway SCAN1 Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Thomas S. Dexheimer
    • 1
  • Shar-yin N. Huang
    • 2
  • Benu Brata Das
    • 2
  • Yves Pommier
    • 2
  1. 1.National Chemical Genomic CenterNational Institutes of HealthRockvilleUSA
  2. 2.Laboratory of Molecular Pharmacology, Center for Cancer ResearchNational Cancer Institute, National Institutes of HealthBethesdaUSA

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