Structural basis of DNA replication fidelity of the Mpox virus
The Mpox virus (MPXV) is an orthopoxvirus that caused a global outbreak in 2022. The poxvirus DNA polymerase complex is responsible for the replication and integrity of the viral genome; however, the molecular mechanisms underlying DNA replication fidelity are still unclear. In this study, we determined the cryoelectron microscopy (cryo-EM) structures of the MPXV F8-A22-E4 polymerase holoenzyme in its editing state, in complex with mismatched primer-template DNA and DNA containing uracil deoxynucleotide. We showed that the MPXV polymerase has a similar replication-to-edit transition mechanism to proofread the mismatched nucleotides like the B-family DNA polymerases of other species. The unique processivity cofactor A22-E4 undergoes conformational changes in different working states and might affect the proofreading process. Moreover, we elucidated the base excision repair (BER) function of E4 as a uracil-DNA glycosylase and the coupling mechanism of genome replication and BER, characteristic of poxviruses. Our findings greatly enhance our molecular understanding of DNA replication fidelity of orthopoxviruses and will stimulate the development of broad-spectrum antiviral drugs.
Authors
- George F. Gao (ORCID: https://orcid.org/0000-0002-3869-615X)
- Han Wang (ORCID: https://orcid.org/0000-0003-0865-8651)
- Yi Shi (ORCID: https://orcid.org/0000-0002-3053-2687)
- Lu Kuai (ORCID: https://orcid.org/0000-0003-3828-8735)
- Yufeng Xie (ORCID: https://orcid.org/0000-0001-9602-0003)
- Qiang Ding (ORCID: https://orcid.org/0000-0002-6226-869X)
- Jianxun Qi (ORCID: https://orcid.org/0000-0002-9358-4732)
- Xiaomei Li (ORCID: https://orcid.org/0000-0002-8870-3186)
- Qi Peng
- Qian Wang (ORCID: https://orcid.org/0000-0003-0293-7369)
Institutions
- King University (US)
- Academy of Medical Sciences (GB)
- Chinese Academy of Sciences (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Peking University (CN)
- The World Academy of Sciences (IT)
- Shanxi Academy of Building Research (CN)
- Czech Academy of Sciences, Institute of Microbiology (CZ)
- Institute of Microbiology (CN)
- Early Warning (United States) (US)
- Beijing Academy of Science and Technology (CN)
- University of Chinese Academy of Sciences (CN)
- Tsinghua University (CN)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-03-04
- DOI
- https://doi.org/10.1073/pnas.2411686122
- Citations
- 7
- Primary Topic
- Poxvirus research and outbreaks
- Type
- article
- Field-Weighted Citation Impact
- 7.25
Funders
- National Natural Science Foundation of China
- National Key Research and Development Program of China