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Although the virus-encoded replication-associated protein (Rep\/Rep\u2019) plays a critical role in circovirus DNA replication, it lacks polymerase activity. Here, we uncovered a mechanism by which circoviruses hijack the host proliferating cell nuclear antigen (PCNA) via their Rep to recruit POLD1, the catalytic subunit of host DNA polymerase \u03b4, thereby driving viral DNA synthesis. POLD1 was identified to be the major polymerase in the replication of circovirus DNA, and the virus infection promoted POLD1 expression. Further, it had been found that the Rep of Circoviruses bound to host sliding clamp protein PCNA to indirectly recruit POLD1 to viral replication centers, and the N-terminal motif LIXXG of Rep and the C-terminal motif NXNXK of PCNA were identified to be corresponding conservative binding sites. As PCV2 is the most clinically significant circovirus, a small-molecule drug R428 was screened to effectively block the binding between PCV2 Rep and porcine PCNA. R428 could significantly suppress the formation of the Rep\/PCNA complex in cells, and effectively suppress PCV2 replication and alleviate PCV2 infection-induced tissue damage in mice and piglets. In conclusion, we elucidated the novel mechanism by which circoviruses hijack host PCNA-POLD1 to facilitate their DNA replication via Rep, and identified R428 as a potential anti-PCV2 agent for the prevention and control of circovirus-associated diseases.<\/jats:p>","DOI":"10.1371\/journal.ppat.1014575","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:35:44Z","timestamp":1790616944000},"page":"e1014575","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hijacking of host PCNA by circovirus replication-associated protein to recruit POLD1 drives viral DNA replication and is inhibited by R428"],"prefix":"10.1371","volume":"22","author":[{"given":"Lei","family":"Zhu","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine, Northwest A&F University","place":["Yangling, 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Ministry of Education, School of Life Science and Technology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Huang","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Northwest A&F University","place":["Yangling, China"]},{"name":"Engineering Research Center of Efficient New Vaccines for Animals, Ministry of Education","place":["Yangling, China"]},{"name":"Key Laboratory of Ruminant Disease Prevention and Control (West), Ministry of Agriculture and Rural Affairs","place":["Yangling, China"]},{"name":"Engineering Research Center of Efficient New Vaccines for Animals, Universities of Shaanxi Province","place":["Yangling, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dewen","family":"Tong","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Northwest A&F University","place":["Yangling, China"]},{"name":"Engineering Research Center of Efficient New Vaccines for Animals, 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