Tyrosyl-DNA Phosphodiesterase as a Target for Anticancer Therapy

ISSN: 1875-5992 (Online)
ISSN: 1871-5206 (Print)


Volume 16, 12 Issues, 2016


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Anti-Cancer Agents in Medicinal Chemistry

Formerly: Current Medicinal Chemistry - Anti-Cancer Agents

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  • 27th of 59 in Chemistry, Medicinal

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Editor-in-Chief:
Michelle Prudhomme
Universite Blaise Pascal - C.N.R.S
Aubiere Cedex
France


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Tyrosyl-DNA Phosphodiesterase as a Target for Anticancer Therapy



Anti-Cancer Agents in Medicinal Chemistry, 8(4): 381-389.

Author(s): Thomas S. Dexheimer, Smitha Antony, Christophe Marchand and Yves Pommier.

Affiliation: Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr., Building 37, Room 5068, Bethesda,Maryland, 20892-4255, USA.

Abstract

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a recently discovered enzyme that catalyzes the hydrolysis of 3-phosphotyrosyl bonds. Such linkages form in vivo following the DNA processing activity of topoisomerase I (Top1). For this reason, Tdp1 has been implicated in the repair of irreversible Top1-DNA covalent complexes, which can be generated by either exogenous or endogenous factors. Tdp1 has been regarded as a potential therapeutic co-target of Top1 in that it seemingly counteracts the effects of Top1 inhibitors, such as camptothecin and its clinically used derivatives. Thus, by reducing the repair of Top1-DNA lesions, Tdp1 inhibitors have the potential to augment the anticancer activity of Top1 inhibitors provided there is a presence of genetic abnormalities related to DNA checkpoint and repair pathways. Human Tdp1 can also hydrolyze other 3-end DNA alterations including 3-phosphoglycolates and 3-abasic sites indicating it may function as a general 3-DNA phosphodiesterase and repair enzyme. The importance of Tdp1 in humans is highlighted by the observation that a recessive mutation in the human TDP1 gene is responsible for the inherited disorder, spinocerebellar ataxia with axonal neuropathy (SCAN1). This review provides a summary of the biochemical and cellular processes performed by Tdp1 as well as the rationale behind the development of Tdp1 inhibitors for anticancer therapy.


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Article Details

Volume: 8
Issue Number: 4
First Page: 381
Last Page: 389
Page Count: 9
DOI: 10.2174/187152008784220357
Price: $58
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