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Cited by 426

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Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1

Open access
El-Khamisy, Sherif F., Saifi, Gulam M., Weinfeld, Michael, Johansson, Fredrik, Helleday, Thomas, Lupski, James R., Caldecott, Keith W.·2005·Nature
DOI 10.1038/nature03314
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Abstract

Spinocerebellar ataxia with axonal neuropathy-1 (SCAN1) is a neurodegenerative disease that results from mutation of tyrosyl phosphodiesterase 1 (TDP1). In lower eukaryotes, Tdp1 removes topoisomerase 1 (top1) peptide from DNA termini during the repair of double-strand breaks created by collision of replication forks with top1 cleavage complexes in proliferating cells. Although TDP1 most probably fulfils a similar function in human cells, this role is unlikely to account for the clinical phenotype of SCAN1, which is associated with progressive degeneration of post-mitotic neurons. In addition, this role is redundant in lower eukaryotes, and Tdp1 mutations alone confer little phenotype. Moreover, defects in processing or preventing double-strand breaks during DNA replication are most probably associated with increased genetic instability and cancer, phenotypes not observed in SCAN1 (ref. 8). Here we show that in human cells TDP1 is required for repair of chromosomal single-strand breaks arising independently of DNA replication from abortive top1 activity or oxidative stress. We report that TDP1 is sequestered into multi-protein single-strand break repair (SSBR) complexes by direct interaction with DNA ligase IIIα and that these complexes are catalytically inactive in SCAN1 cells. These data identify a defect in SSBR in a neurodegenerative disease, and implicate this process in the maintenance of genetic integrity in post-mitotic neurons.

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Research works printed but not linked: 29

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Metadata

Authors
El-Khamisy, S. F., Saifi, G. M., Weinfeld, M., Johansson, F., Helleday, T., Lupski, J. R., & Caldecott, K. W.
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2005-03
Volume
434
Issue
7029
Pages
108-113
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature03314
OpenAlex
W2072358340
Cited by
426
References
1
FWCI
9.68
Type
journal article
Language
en
Open access
green
Licence
www.springer.com/tdm (tdm)

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CoChat. (2026). Citation check: Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1. https://app.cochat.ai/papers/10.1038/nature03314
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El-Khamisy, S. F., Saifi, G. M., Weinfeld, M., Johansson, F., Helleday, T., Lupski, J. R., & Caldecott, K. W. (2005). Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1. Nature. https://doi.org/10.1038/nature03314

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