{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent studies have revealed that a tyrosyl‐DNA phosphodiesterase—often referred to as TDP2 (also known as TTRAP/EAPII)—plays a central role in maintaining genome integrity. In mammalian cells, TDP2 facilitates the repair of DNA double‐strand breaks arising from abortive topoisomerase activities. For instance, in the context of topoisomerase I–mediated damage, loss‐of‐function models demonstrate that although TDP1 is the primary enzyme responsible for hydrolyzing 3′‐phosphotyrosyl bonds, TDP2 can partially compensate when TDP1 is absent."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Moreover, in response to topoisomerase II poisons that induce TOP2-linked double-strand breaks, TDP2 liberates DNA termini to enable error-free non-homologous end joining, a mechanism that is vital for accurate DSB repair and the preservation of genome stability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Structural studies have further illuminated a single Mg²⁺-ion catalytic mechanism underlying TDP2 function, substantiating its essential enzymatic role."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its DNA repair activities, this enzyme functions as an adaptor molecule in non-canonical signaling pathways. Specifically, ligand-activated TGF‑β receptors have been shown to recruit TTRAP, which in turn associates with signaling components such as the TRAF6–TAK1 complex. This interaction modulates downstream responses, including activation of p38 MAP kinase and NF‑κB, thereby influencing TGF‑β–induced apoptotic processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTDP2 also contributes to viral pathogenesis by processing covalent linkages between viral proteins and genomic RNA. During infection by picornaviruses, its activity is necessary for removing the VPg protein from the 5′-end of viral RNAs, with differential dependency observed among virus species."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Finally, although one study focused on sperm retrieval in azoospermic men hints at the potential clinical relevance of predictive biomarkers in reproductive medicine, the specific role of this enzyme—or a putative related factor referred to as SPEM1—in spermatogenesis remains to be clarified."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Zhihong Zeng, Abhishek Sharma, Limei Ju, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TDP2 promotes repair of topoisomerase I-mediated DNA damage in the absence of TDP1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gks622"}], "href": "https://doi.org/10.1093/nar/gks622"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22740648"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22740648"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Fernando Gómez-Herreros, Rocío Romero-Granados, Zhihong Zeng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TDP2-dependent non-homologous end-joining protects against topoisomerase II-induced DNA breaks and genome instability in cells and in vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1003226"}], "href": "https://doi.org/10.1371/journal.pgen.1003226"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23505375"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23505375"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Matthew J Schellenberg, Lalith Perera, Christina N Strom, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reversal of DNA damage induced Topoisomerase 2 DNA-protein crosslinks by Tdp2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gkw228"}], "href": "https://doi.org/10.1093/nar/gkw228"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27060144"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27060144"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "György Várady, Balázs Sarkadi, Károly Fátyol "}, {"type": "b", "children": [{"type": "t", "text": "TTRAP is a novel component of the non-canonical TRAF6-TAK1 TGF-β signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0025548"}], "href": "https://doi.org/10.1371/journal.pone.0025548"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21980489"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21980489"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Sonia Maciejewski, Joseph H C Nguyen, Fernando Gómez-Herreros, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Divergent Requirement for a DNA Repair Enzyme during Enterovirus Infections."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "mBio (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/mBio.01931-15"}], "href": "https://doi.org/10.1128/mBio.01931-15"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26715620"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26715620"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Sonia Maciejewski, Wendy Ullmer, Bert L Semler "}, {"type": "b", "children": [{"type": "t", "text": "VPg unlinkase/TDP2 in cardiovirus infected cells: Re-localization and proteolytic cleavage."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Virology (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.virol.2018.01.010"}], "href": "https://doi.org/10.1016/j.virol.2018.01.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29353210"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29353210"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "M-S Hashemi, H Mozdarani, K Ghaedi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Among seven testis-specific molecular markers, SPEM1 appears to have a significant clinical value for prediction of sperm retrieval in azoospermic men."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Andrology (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/andr.12528"}], "href": "https://doi.org/10.1111/andr.12528"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30054974"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30054974"}]}]}]}