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H263A and SCAN1/H493R mutant TDP1 block TOP1-induced double-strand break repair during gene transcription in quiescent cells and promote cell death
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H263A and SCAN1/H493R mutant TDP1 block TOP1-induced double-strand break repair during gene transcription in quiescent cells and promote cell death
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H263A and SCAN1/H493R mutant TDP1 block TOP1-induced double-strand break repair during gene transcription in quiescent cells and promote cell death
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Journal Article
H263A and SCAN1/H493R mutant TDP1 block TOP1-induced double-strand break repair during gene transcription in quiescent cells and promote cell death
2025
Overview
DNA single-strand break (SSB) repair defects lead to hereditary neurological syndromes. Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1), is caused by the homozygous H493R mutation in tyrosyl-DNA phosphodiesterase 1 (TDP1), an enzyme that initiates the repair of DNA topoisomerase 1 (TOP1)-induced SSBs by unlinking the TOP1 peptide from the break. Although TDP1 also initiates the repair of TOP1-induced DNA double-strand breaks (DSBs) associated with transcription, the role of TOP1-induced DSBs in SCAN1 pathology remains unclear. Here, we have addressed the impact of the SCAN1/H493R mutation on the repair of TOP1-induced DSBs. We demonstrate that while TDP1 loss delays the repair of these breaks, SCAN1/H493R completely blocks it in RPE-1 quiescent cells. This blockage is specific to DSBs and is accompanied by a prolonged trapping of mutated TDP1 on DNA, but not of TOP1 cleavage complexes (TOP1cc). Intriguingly, the H263A inactivating mutation of TDP1, which accumulates TOP1cc, also blocks TOP1-induced DSB repair. Importantly, both SCAN1/H493R and H263A mutations exhibit genome instability and cell death. Moreover, we demonstrate that tyrosyl-DNA phosphodiesterase 2 (TDP2) can compensate for TDP1 loss in RPE-1 quiescent cells. Collectively, our data support the potential role of TOP1-induced DSBs as a main contributor to certain hereditary neurological syndromes.
Publisher
Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
Subject
/ 13/106
/ 13/31
/ 14/63
/ 38/44
/ 45/29
/ Ataxia
/ Biomedical and Life Sciences
/ Disease
/ DNA Topoisomerases, Type I - genetics
/ DNA Topoisomerases, Type I - metabolism
/ DNA-Binding Proteins - genetics
/ DNA-Binding Proteins - metabolism
/ Enzymes
/ Genomes
/ Humans
/ Kinases
/ Mutation
/ Peptides
/ Phosphoric Diester Hydrolases - genetics
/ Phosphoric Diester Hydrolases - metabolism
/ Poisons
/ Spinocerebellar Ataxias - genetics
/ Spinocerebellar Ataxias - metabolism
/ Spinocerebellar Ataxias - pathology
/ Yeast
