{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTDP2, also known as TTRAP or EAPII, is a conserved Mg²⁺/Mn²⁺‐dependent phosphodiesterase that is essential for maintaining genome integrity. It acts by directly hydrolyzing 5′-phosphotyrosyl bonds that arise when topoisomerase II becomes aberrantly trapped on DNA during cleavage events. By restoring proper 5′-phosphate termini at these double‐strand breaks, TDP2 enables subsequent repair (typically by non-homologous end joining) and minimizes chromosomal translocations and instability caused by abortive topoisomerase reactions. Detailed biochemical studies have revealed that TDP2 prefers substrates such as single-stranded DNA or duplexes with short overhangs, operates via a two-metal ion mechanism, and is specifically tuned to remove protein adducts generated by topoisomerase II poisons."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its canonical role in the repair of topoisomerase II–induced DNA lesions, TDP2 contributes to several other cellular processes. It participates in viral genome processing by cleaving protein–nucleic acid linkages—for example, releasing the viral polymerase from hepatitis B virus relaxed circular DNA and acting as the VPg unlinkase during picornavirus replication. In parallel, alternative isoforms of TDP2 localize to the mitochondria, where they help preserve organellar genome stability. Its activity is further modulated by regulatory factors such as the SUMO ligase ZATT, ubiquitin interactions that relieve an autoinhibitory state, and phosphorylation (e.g., by ERK3), while its substrate repertoire even extends to processing TOP3B cleavage complexes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, deficits in TDP2 function have far‐reaching consequences. Biallelic loss-of-function mutations in TDP2 are linked to a neurodegenerative syndrome—spinocerebellar ataxia autosomal recessive 23 (SCAR23)—characterized by intellectual disability, seizures, and impaired transcriptional regulation in neurons. Moreover, compromised TDP2 activity increases cellular sensitivity to topoisomerase II–targeting anticancer agents and promotes the formation of aberrant chromosomal rearrangements, underscoring its potential as a therapeutic target. Notably, while TDP2 efficiently resolves topoisomerase-linked DNA adducts in somatic cells, it is unable to process protein-linked breaks generated during meiosis (such as those involving Spo11), highlighting distinct repair requirements in different cellular contexts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Felipe Cortes Ledesma, Sherif F El Khamisy, Maria C Zuma, et al. 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