{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTOP3B is a unique type IA topoisomerase endowed with dual activity toward both DNA and RNA substrates, ensuring proper nucleic acid topology during critical cellular processes. In the nucleus, TOP3B is recruited—often via its partner TDRD3—to regions such as the c-MYC promoter, where it relaxes excessive negative supercoiling and resolves transcription‐generated R-loops. This activity not only promotes efficient gene transcription but also protects against DNA damage, genomic instability, and chromosomal translocations that can lead to cancer. Furthermore, the enzyme’s catalytic function is modulated by post-translational modifications such as arginine methylation, which fine-tunes its activity and interactions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its DNA topoisomerase role, TOP3B displays robust RNA topoisomerase activity that is fundamental for mRNA metabolism and translation. It directly binds mRNAs through a distinct RNA-binding domain to associate with the translation machinery—including polyribosomes—and works together with factors such as TDRD3 and FMRP to regulate synapse formation and neurodevelopment. This dual functionality is evolutionarily conserved and extends to broader biological contexts, as TOP3B is critical for the replication of positive-sense RNA viruses. Disruption in TOP3B function has been associated with a spectrum of neurodevelopmental disorders, ranging from schizophrenia and autism spectrum disorders to epilepsy."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe regulation and expression of TOP3B are controlled at multiple levels. Its gene promoter, which is characterized by a high GC-content and key activator elements, ensures efficient transcription, while alternative isoforms exhibit distinct subcellular localizations that tailor function to specific cellular compartments. Clinically, aberrant TOP3B expression is linked to adverse outcomes in breast cancer, and genetic alterations—including deletions and copy number variants affecting TOP3B—have been implicated in various neurodevelopmental disorders such as epilepsy and autism. Moreover, innovative studies reveal a dedicated repair pathway for TOP3B cleavage complexes involving ubiquitination and proteasomal processing, emphasizing its pivotal role in maintaining genomic and transcriptomic homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "15"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yanzhong Yang, Kevin M McBride, Sean Hensley, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Arginine methylation facilitates the recruitment of TOP3B to chromatin to prevent R loop accumulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2014.01.011"}], "href": "https://doi.org/10.1016/j.molcel.2014.01.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24507716"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24507716"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Lifeng Huang, Zhihao Wang, Nithya Narayanan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Arginine methylation of the C-terminus RGG motif promotes TOP3B topoisomerase activity and stress granule localization."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gky103"}], "href": "https://doi.org/10.1093/nar/gky103"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29471495"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29471495"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Tao Zhang, Mathew Wallis, Vida Petrovic, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of TOP3B leads to increased R-loop formation and genome instability."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Open Biol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1098/rsob.190222"}], "href": "https://doi.org/10.1098/rsob.190222"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31795919"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31795919"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Muzammil Ahmad, Yutong Xue, Seung Kyu Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RNA topoisomerase is prevalent in all domains of life and associates with polyribosomes in animals."}]}, {"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/gkw508"}], "href": "https://doi.org/10.1093/nar/gkw508"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27257063"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27257063"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Muzammil Ahmad, Weiping Shen, Wen Li, et al. 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