Journal Article

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

Caldecott, Keith W., Saifi, Gulam M., Weinfeld, Michael, Lupski, James R., Helleday, Thomas, El-Khamisy, Sherif F., Johansson, Fredrik

2005

Overview

Ataxia cause identified An investigation into the molecular basis of the disease SCAN1 (spinocerebellar ataxia with axonal neuropathy-1) has identified for the first time a defect in the repair of chromosomal single-strand breaks in a neurodegenerative disease. The disease results from mutations in tyrosyl phosphodiesterase 1, but the known function of this enzyme — repairing double-strand breaks during replication — seemed unlikely to cause the observed pathology. The new study reveals a second function for the enzyme in human cells: repairing chromosome breaks caused by oxidative stress in post-mitotic neurons, and it is this that is likely to cause the symptoms of SCAN-1. Spinocerebellar ataxia with axonal neuropathy-1 (SCAN1) is a neurodegenerative disease that results from mutation of tyrosyl phosphodiesterase 1 (TDP1) 1 . 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 2 , 3 , 4 . 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 4 , 5 , 6 , 7 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: 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 / Humanities and Social Sciences / Humans / letter / Medical sciences / multidisciplinary / 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 / Science / Science (multidisciplinary) / Spinocerebellar Ataxias - genetics / Spinocerebellar Ataxias - pathology / Spinocerebellar Ataxias/genetics/pathology / Topoisomerase I Inhibitors / Xenopus Proteins