Defective DNA Single-Strand Break Repair in Spinocerebellar Ataxia With Axonal Neuropathy-1

摘要

Spinocerebellar ataxia with axonal neuropathy-1 (SCAN1) is a neurodegenerative disease that is caused by homozygous mutations in the tyrosyl phosphodiesterase 1 gene (TDP1). TDP1 was known to be essential for the repair of DNA double-strand breaks created by topoisomerase 1 (top1) occurring at DNA replication forks in proliferating cells of lower eukaryotes. This article shows that TDP1 is required for the repair of single-strand breaks (SSBs) that arise independent of replication, as cells from SCAN1 patients incur DNA SSBs by abortive top1 activity or oxidative stress. The authors reveal that TDP1 is involved in the multiprotein single-strand break repair (SSBR) process through direct interaction with DNA ligase III alpha, which repairs top1-induced SSBs. Although complexes are formed, the SSBR process is inactive in SCAN1 cells. This links SSBR to neurodegenerative disease.