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

• Published in: Nature Vol. 434; no. 7029; pp. 108 - 113
• Main Authors: Weinfeld, Michael, Helleday, Thomas, Lupski, James R, Caldecott, Keith W, El-Khamisy, Sherif F, Johansson, Fredrik, Saifi, Gulam M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 03.03.2005; Nature Publishing Group
• Subjects: Axons - metabolism; Axons - pathology; Axons/metabolism/pathology; Biological and medical sciences; Camptothecin - pharmacology; Catalysis - drug effects; Cell Line; Comet Assay; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Deoxyribonucleic acid; DNA; DNA Damage - drug effects; DNA Ligase ATP; DNA Ligases - metabolism; DNA Repair - drug effects; DNA Replication - drug effects; DNA Topoisomerases, Type I - metabolism; DNA, Single-Stranded - genetics; DNA, Single-Stranded - metabolism; Eukaryotes; Humans; Medical sciences; Multiprotein Complexes - chemistry; Multiprotein Complexes - metabolism; Multiprotein Complexes/chemistry/metabolism; Mutation; Neurological disorders; Neurology; Neurons; Oxidative stress; Oxidative Stress - physiology; Peptides; Phosphoric Diester Hydrolases - genetics; Phosphoric Diester Hydrolases - metabolism; Phosphoric Diester Hydrolases/genetics/metabolism; Poly-ADP-Ribose Binding Proteins; Protein Binding; Spinocerebellar Ataxias - genetics; Spinocerebellar Ataxias - pathology; Spinocerebellar Ataxias/genetics/pathology; Topoisomerase I Inhibitors; Xenopus Proteins; Spinocerebellar heredodegeneration; Oxidative stress; Nervous system diseases; Pathogenesis; DNA; Central nervous system disease; Replication; Degenerative disease; Spinal cord disease; Cerebral disorder; Genetic disease; Type I/antagonists & inhibitors/metabolism; DNA Topoisomerases; Single-Stranded/genetics/metabolism
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature03314

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.