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A prominent example is dU\u2010DNA, where thymidine is globally replaced with 2\u2032\u2010deoxyuridine. Despite its widespread occurrence, dU\u2010DNA's biosynthetic pathways and functional roles remain incompletely understood. Here, different enzymes supporting dU\u2010DNA biosynthesis in phage PBS1, Roseophage DSS3_VP1, and Yersiniophage PhiR1\u201037 are identified and characterized. The dU nucleotide precursor is supplied by phage dCTP deaminases (Dcds). Thymidine nucleotides are degraded by dTMP phosphatases (Dtms) in PBS1 and DSS3_VP1, and by a dTTP pyrophosphatase (Dtt) in PhiR1\u201037, preventing incorporation into phage DNA. The dU\u2010DNA, isolated from Yersiniophage PhiR1\u201037 or synthesized by PCR, demonstrates resistance to cleavage by restriction enzymes recognizing thymidine\u2010containing sequences, partial resistance to\n                    <jats:italic>Lb<\/jats:italic>\n                    Cas12a nuclease recognizing a TTTV PAM site, while remaining sensitive to\n                    <jats:italic>Sp<\/jats:italic>\n                    Cas9 nuclease recognizing a NGG PAM site. A phylogenetic analysis of PBS1 dCTP deaminase and closely related T4 phage dCMP deaminase suggest possible evolutionary origins from bacterial dCDP deaminases. Overall, these findings suggest independent acquisition of dU\u2010DNA biosynthetic enzymes and pathways in the diverse phages, and support its protective function against different host\u2010encoded nucleases.\n                  <\/jats:p>","DOI":"10.1002\/advs.202512937","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T10:10:03Z","timestamp":1758881403000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Distinct Phage\u2010Encoded Enzymes for Substitution of Deoxythymidine by Deoxyuridine in Phage Genomes"],"prefix":"10.1002","volume":"12","author":[{"given":"Yating","family":"Li","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory of Zoonosis Yangzhou University  Yangzhou 225009 China"},{"name":"Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality Ministry of Agriculture of China Yangzhou University  Yangzhou 225009 China"},{"name":"Jiangsu Co\u2010Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses Yangzhou University  Yangzhou Jiangsu Province 225009 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason","family":"Tan","sequence":"additional","affiliation":[{"name":"Singapore Institute of Food and Biotechnology Innovation (SIFBI) Agency for Science Technology and Research (A*STAR)  Singapore 138669 Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanqin","family":"Tu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Zoonosis Yangzhou University  Yangzhou 225009 China"},{"name":"Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality Ministry of Agriculture of China Yangzhou University  Yangzhou 225009 China"},{"name":"Jiangsu Co\u2010Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses Yangzhou University  Yangzhou Jiangsu Province 225009 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingnan","family":"Wu","sequence":"additional","affiliation":[{"name":"College of Bioscience and Biotechnology Yangzhou University  Yangzhou Jiangsu Province 225009 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zaifang","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Bioscience and Biotechnology Yangzhou University  Yangzhou Jiangsu Province 225009 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yifeng","family":"Wei","sequence":"additional","affiliation":[{"name":"Singapore Institute of Food and Biotechnology Innovation (SIFBI) Agency for Science Technology and Research (A*STAR)  Singapore 138669 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Origin) for Agrifood Safety and Quality Ministry of Agriculture of China Yangzhou University  Yangzhou 225009 China"},{"name":"Jiangsu Co\u2010Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses Yangzhou University  Yangzhou Jiangsu Province 225009 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