TDP1 (tyrosyl-DNA phosphodiesterase 1) is a DNA repair enzyme that primarily functions to remove covalent protein-DNA adducts through hydrolysis of 3'-phosphodiester bonds 1. TDP1 excises trapped topoisomerase I complexes in both nuclear and mitochondrial compartments, and also repairs oxidative damage-induced 3'-phosphoglycolates and alkylation-induced DNA breaks 1. The enzyme coordinates with base excision repair pathway proteins including PARP1, XRCC1, and ligase III 1. TDP1 is particularly critical for transcriptional genome stability; its dysfunction causes accumulation of transcription-blocking topoisomerase I complexes that generate double-strand breaks, especially in non-replicating cells 23. Mutations in TDP1 cause SCAN1 (spinocerebellar ataxia with axonal neuropathy 1), a neurodegenerative syndrome resulting from impaired repair of transcriptional DNA breaks 3. The H493R SCAN1 mutation exhibits gain-of-function properties that paradoxically prevent backup DSB repair pathways 3. TDP1 also processes DNA-protein cross-links arising from abasic sites 4 and contributes to tolerance of topoisomerase-targeting anticancer drugs, with TDP1 variants influencing both drug toxicity and therapeutic response 5.