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During B cell development, activation-induced cytidine deaminase (AID) generates uracils in DNA, which UNG processes in an error-prone fashion to accomplish immunoglobulin (Ig) somatic hypermutation or class switch recombination (CSR). The mechanism that governs high-fidelity versus mutagenic uracil repair is not understood. The B cell tropic murine Gammaherpesvirus 68 (MHV68\/MHV-4) encodes a functional homolog of UNG that can process AID-induced genomic uracils. MHV68UNG did not support hypermutation, suggesting intrinsic properties of UNG influence repair outcome. Noting the structural divergence between the UNGs, we define the RPA-interacting motif as a determinant of mutation outcome. UNG or RPA mutants unable to interact support only high-fidelity repair. In B cells, transversions at the Ig variable region are decreased, while CSR is supported. Thus UNG\u2013RPA governs the generation of mutations and has implications for locus-specific mutagenesis in B cells and deamination-associated mutational signatures in cancer.<\/jats:p>","DOI":"10.1093\/nar\/gkag441","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T11:42:38Z","timestamp":1777030958000},"source":"Crossref","is-referenced-by-count":0,"title":["UNG\u2013RPA interaction governs the choice between high-fidelity and mutagenic uracil repair"],"prefix":"10.1093","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9754-2129","authenticated-orcid":false,"given":"Yunxiang","family":"Mu","sequence":"first","affiliation":[{"name":"Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center , Houston, TX77054 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zaowen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center , Houston, TX77054 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua B","family":"Plummer","sequence":"additional","affiliation":[{"name":"Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center , Houston, TX77054 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7373-7631","authenticated-orcid":false,"given":"Monika A","family":"Zelazowska","sequence":"additional","affiliation":[{"name":"Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center , Houston, TX77054 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiwen","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Stony Brook University , Stony Brook, NY 11794 ,","place":["United States"]},{"name":"Molecular and Cellular Biology Program, Stony Brook University , Stony Brook, NY 11794 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9648-522X","authenticated-orcid":false,"given":"Laurie T","family":"Krug","sequence":"additional","affiliation":[{"name":"HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, MD 20892 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9646-152X","authenticated-orcid":false,"given":"Kevin M","family":"McBride","sequence":"additional","affiliation":[{"name":"Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center , Houston, TX77054 ,","place":["United 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