Hijacking of host PCNA by circovirus replication-associated protein to recruit POLD1 drives viral DNA replication and is inhibited by R428
5 affiliations
- 1College of Veterinary Medicine, Northwest A&F University, Yangling, China
- 2Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, China
- 3Engineering Research Center of Efficient New Vaccines for Animals, Ministry of Education, Yangling, China
- 4Key Laboratory of Ruminant Disease Prevention and Control (West), Ministry of Agriculture and Rural Affairs, Yangling, China
- 5Engineering Research Center of Efficient New Vaccines for Animals, Universities of Shaanxi Province, Yangling, China
Abstract
Circoviruses are the smallest known mammalian viruses with a single-stranded circular genome, whose replication capacity is highly dependent on host factors. Although the virus-encoded replication-associated protein (Rep/Rep’) 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 δ, 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. Author summary: Circoviruses are major economic pathogens in the animal industry and pose a potential threat to humans. The widely used porcine circovirus type 2 (PCV2) vaccines cannot fully prevent virus spread, and no vaccines are currently available for other circoviruses. Therefore, elucidating their replication mechanism may provide suitable strategies for the prevention and control of these viruses. Considering that circoviruses rely on the host enzyme system for replication, we screened host polymerases involved in circovirus DNA replication and found that POLD1, the catalytic subunit of host DNA polymerase δ, is the major polymerase involved. Further research revealed that circoviruses hijack host proliferating cell nuclear antigen (PCNA) via their replication-associated protein (Rep) to recruit POLD1, and the N-terminal motif LIXXG of Rep and the C-terminal motif NXNXK of PCNA were identified as the conserved binding sites. Based on these findings, a small-molecule drug, R428, was found to be effective in blocking the binding between PCV2 Rep and porcine PCNA. In summary, this study revealed that circoviruses utilize Rep to hijack host POLD1 through PCNA, thereby promoting their DNA replication, and identified R428 as a potential anti-PCV2 agent for controlling circovirus-associated diseases.
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BibTeX
@article{zhu2026hijacking,
title = {{Hijacking of host PCNA by circovirus replication-associated protein to recruit POLD1 drives viral DNA replication and is inhibited by R428}},
author = {Lei Zhu and Guan Zhang and Yingying Pu and Wenyu Wang and Zhanyan Zhang and Jiasai Kang and Haoshu Zhang and Lingling Chang and Le Shi and Yong Huang and Dewen Tong and Qian Du},
journal = {PLOS Pathogens},
year = {2026},
month = sep,
doi = {10.1371/journal.ppat.1014575},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014575},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Hijacking of host PCNA by circovirus replication-associated protein to recruit POLD1 drives viral DNA replication and is inhibited by R428
AU - Lei Zhu
AU - Guan Zhang
AU - Yingying Pu
AU - Wenyu Wang
AU - Zhanyan Zhang
AU - Jiasai Kang
AU - Haoshu Zhang
AU - Lingling Chang
AU - Le Shi
AU - Yong Huang
AU - Dewen Tong
AU - Qian Du
PY - 2026
DA - 2026/09/28
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014575
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014575
AB - Circoviruses are the smallest known mammalian viruses with a single-stranded circular genome, whose replication capacity is highly dependent on host factors. Although the virus-encoded replication-associated protein (Rep/Rep’) 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 δ, 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. Author summary: Circoviruses are major economic pathogens in the animal industry and pose a potential threat to humans. The widely used porcine circovirus type 2 (PCV2) vaccines cannot fully prevent virus spread, and no vaccines are currently available for other circoviruses. Therefore, elucidating their replication mechanism may provide suitable strategies for the prevention and control of these viruses. Considering that circoviruses rely on the host enzyme system for replication, we screened host polymerases involved in circovirus DNA replication and found that POLD1, the catalytic subunit of host DNA polymerase δ, is the major polymerase involved. Further research revealed that circoviruses hijack host proliferating cell nuclear antigen (PCNA) via their replication-associated protein (Rep) to recruit POLD1, and the N-terminal motif LIXXG of Rep and the C-terminal motif NXNXK of PCNA were identified as the conserved binding sites. Based on these findings, a small-molecule drug, R428, was found to be effective in blocking the binding between PCV2 Rep and porcine PCNA. In summary, this study revealed that circoviruses utilize Rep to hijack host POLD1 through PCNA, thereby promoting their DNA replication, and identified R428 as a potential anti-PCV2 agent for controlling circovirus-associated diseases.
SN - 1553-7374
ER -