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

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posted on 2023-06-07, 20:40 authored by Sherif F El-Khamisy, Gulam M Saifi, Michael Weinfeld, Fredrik Johansson, Thomas Helleday, James R Lupski, Keith CaldecottKeith Caldecott
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 cells2, 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 phenotype4, 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 IIIa 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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  • Sussex Centre for Genome Damage Stability Publications


This is the work of my PhD student (Sherif E-K). I am the senior and corresponding author. All of the experiments in this publication were conducted in my lab by Sherif E-K. Other authors provided materials and, in one case (FJ/TH) a supplementary figure.

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