{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUracil‐DNA glycosylase (UNG) plays a pivotal role in maintaining genomic integrity by excising uracil bases that arise either from the deamination of cytosine or from misincorporation of dUTP during DNA replication. This excision initiates the base excision repair (BER) pathway, thereby preventing mutagenic C:G to T:A transition events. In addition, UNG is critical for adaptive immunity as it facilitates both class‐switch recombination and somatic hypermutation in immunoglobulin genes—processes whose impairment is linked to hyper‐IgM syndromes and defective antibody diversification. Germline variations in UNG, along with other BER components, have also been implicated in disease susceptibility."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nUNG’s activity is intricately regulated by its biochemical environment and its association with other proteins. The nuclear isoform, UNG2, exhibits robust activity in replication foci and is modulated by cell cycle–dependent phosphorylation events and by interactions with key replication factors such as proliferating cell nuclear antigen (PCNA) and XRCC1. Structural and kinetic studies indicate that UNG utilizes a facilitated diffusion mechanism along the DNA—sliding over the phosphodiester backbone independently of a continuous negative charge—to rapidly sample millions of base pairs for the rare uracil lesion. In parallel, distinct isoforms (such as mitochondrial UNG1) ensure the repair of uracils in organellar DNA, while phosphatases like PPM1D modulate UNG2 activity via dephosphorylation to fine‐tune DNA repair during and after replication."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPathogens have evolved strategies to counteract or co‐opt UNG function in order to modulate host DNA repair and immune responses. For example, viral accessory proteins such as HIV‐1 Vpr and KSHV LANA interact with or promote the degradation of UNG2 via recruitment of host ubiquitin ligase complexes, thereby influencing the processing of deaminated viral DNA and, in some cases, protecting the viral genome from excessive mutation. In parallel, APOBEC3 family deaminases introduce uracils into viral cDNA, a process ultimately modulated by UNG activity that affects viral mutagenesis and replication fidelity. Collectively, these studies underscore the multifaceted role of UNG—not only as a guardian against genomic instability and a facilitator of antibody maturation, but also as a modulated factor in virus–host interactions that can be subverted to influence infection outcomes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kohsuke Imai, Geir Slupphaug, Wen-I Lee, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "B cells from hyper-IgM patients carrying UNG mutations lack ability to remove uracil from ssDNA and have elevated genomic uracil."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20050042"}], "href": "https://doi.org/10.1084/jem.20050042"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15967827"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15967827"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Peter Broderick, Tina Bagratuni, Jairam Vijayakrishnan, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Uracil-DNA glycosylase in base excision repair and adaptive immunity: species differences between man and mouse."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M111.230052"}], "href": "https://doi.org/10.1074/jbc.M111.230052"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21454529"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21454529"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Bodil Kavli, Ottar Sundheim, Mansour Akbari, et al. 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