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SCAN1 mutant Tdp1 accumulates the enzyme–DNA intermediate and causes camptothecin hypersensitivity
Journal article   Open access   Peer reviewed

SCAN1 mutant Tdp1 accumulates the enzyme–DNA intermediate and causes camptothecin hypersensitivity

Heidrun Interthal, Hong Jing Chen, Thomas E Kehl-Fie, Jörg Zotzmann, John B Leppard and James J Champoux
The EMBO journal, Vol.24(12), pp.2224-2233
06/15/2005
DOI: 10.1038/sj.emboj.7600694
PMCID: PMC1150888
PMID: 15920477
url
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1150888View
Published (Version of record) Open Access

Abstract

Tyrosyl‐DNA phosphodiesterase (Tdp1) catalyzes the hydrolysis of the tyrosyl‐3′ phosphate linkage found in topoisomerase I–DNA covalent complexes. The inherited disorder, spinocerebellar ataxia with axonal neuropathy (SCAN1), is caused by a H493R mutation in Tdp1. Contrary to earlier proposals that this disease results from a loss‐of‐function mutation, we show here that this mutation reduces enzyme activity ∼25‐fold and importantly causes the accumulation of the Tdp1–DNA covalent reaction intermediate. Thus, the attempted repair of topoisomerase I–DNA complexes by Tdp1 unexpectedly generates a new protein–DNA complex with an apparent half‐life of ∼13 min that, in addition to the unrepaired topoisomerase I–DNA complex, may interfere with transcription and replication in human cells and contribute to the SCAN1 phenotype. The analysis of Tdp1 mutant cell lines derived from SCAN1 patients reveals that they are hypersensitive to the topoisomerase I‐specific anticancer drug camptothecin (CPT), implicating Tdp1 in the repair of CPT‐induced topoisomerase I damage in human cells. This finding suggests that inhibitors of Tdp1 could act synergistically with CPT in anticancer therapy.
 DNA repair phospholipase D SCAN1 topoisomerase I tyrosyl‐DNA phosphodiesterase

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