H263A and SCAN1/H493R mutant TDP1 block TOP1-induced double-strand break repair during gene transcription in quiescent cells and promote cell death.

ABSTRACT: 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

SUBMITTER: Rubio-Contreras D 

PROVIDER: S-EPMC12663148 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature