TOP3A encodes DNA topoisomerase III alpha, an essential enzyme that relieves topological stress during DNA replication and transcription by introducing transient single-strand breaks in DNA 1. The enzyme functions through a reversible cleavage mechanism, forming covalent TOP3A-DNA protein crosslinks (TOP3A-DPCs) at the 5'-end of single-strand breaks before resealing the DNA 2. As a component of the BLM-TOP3A-RMI (BTR) complex, TOP3A plays critical roles in homologous recombination and chromosome 17 3. TOP3A is particularly important for mitochondrial DNA metabolism, being required for mtDNA decatenation and segregation after replication completion 2. In cancer biology, TOP3A shows distinct functions in alternative lengthening of telomeres (ALT), where it enriches at telomeres of ALT cancer cells and promotes telomeric RNA accumulation and single-stranded telomeric DNA generation 4. During mitosis, TOP3A participates in telomere deprotection mechanisms that activate DNA damage responses 5. Disease associations include microcephaly syndromes and mitochondrial disorders, reflecting its dual nuclear and mitochondrial functions. Repair of persistent TOP3A-DPCs involves multiple pathways including PARP1-FEN1 and ubiquitin-SPRTN mechanisms 6.