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

El-Khamisy, S. F., Saifi, G. M., Weinfeld, M., Johansson, F., Helleday, T., Lupski, J. R. and Caldecott, K. W. (2005) Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1. Nature, 434 (7029). pp. 108-13. ISSN 1476-4687

Full text not available from this repository.


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 IIIalpha 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.

Item Type: Article
Additional Information: 1476-4687 Journal Article GDSC126
Keywords: Axons/metabolism/*pathology Camptothecin/pharmacology Catalysis/drug effects Cell Line Comet Assay *DNA Damage/drug effects DNA Ligases/metabolism *DNA Repair/drug effects DNA Replication/drug effects DNA Topoisomerases, Type I/antagonists & inhibitors/metabolism DNA, Single-Stranded/genetics/*metabolism Humans Multiprotein Complexes/chemistry/metabolism Mutation Oxidative Stress/physiology Phosphoric Diester Hydrolases/genetics/metabolism Protein Binding Research Support, Non-U.S. Gov't Spinocerebellar Ataxias/*genetics/*pathology
Schools and Departments: School of Life Sciences
School of Life Sciences > Biochemistry
Depositing User: Gee Wheatley
Date Deposited: 19 Mar 2007
Last Modified: 30 Nov 2012 16:51
Google Scholar:153 Citations
📧 Request an update