Nsp1 stalls DNA polymerase α at DNA hairpins
Abstract The human primosome, a four-subunit complex of DNA primase and DNA polymerase alpha (Polα), plays a critical role in DNA replication by initiating RNA and DNA synthesis on both chromosome strands. A recent study has shown that a major virulence factor in the SARS-CoV-2 infection, Nsp1 (non-...
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Nature Portfolio
2025-05-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-00982-8 |
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| author | Andrey G. Baranovskiy Lucia M. Morstadt Nigar D. Babayeva Tahir H. Tahirov |
| author_facet | Andrey G. Baranovskiy Lucia M. Morstadt Nigar D. Babayeva Tahir H. Tahirov |
| author_sort | Andrey G. Baranovskiy |
| collection | DOAJ |
| description | Abstract The human primosome, a four-subunit complex of DNA primase and DNA polymerase alpha (Polα), plays a critical role in DNA replication by initiating RNA and DNA synthesis on both chromosome strands. A recent study has shown that a major virulence factor in the SARS-CoV-2 infection, Nsp1 (non-structural protein 1), forms a stable complex with Polα but does not affect primosome activity. Here we show that Nsp1 inhibits DNA synthesis across inverted repeats prone to hairpin formation. Analysis of current structural data revealed the overlapping binding sites for Nsp1 and the winged helix-turn-helix domain of RPA (wHTH) on Polα, pointing to a potential competition between them. Comparison of the inhibitory effect of Nsp1 and wHTH on DNA hairpin bypass by Polα showed an eightfold lower IC50 value for Nsp1 (1 µM). This study provides valuable insight into the mechanism of inhibition of human DNA replication by Nsp1 during a SARS-CoV-2 infection. |
| format | Article |
| id | doaj-art-97c3ecbc8d5e43e3a188a086b854bd42 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-97c3ecbc8d5e43e3a188a086b854bd422025-08-20T03:48:18ZengNature PortfolioScientific Reports2045-23222025-05-011511710.1038/s41598-025-00982-8Nsp1 stalls DNA polymerase α at DNA hairpinsAndrey G. Baranovskiy0Lucia M. Morstadt1Nigar D. Babayeva2Tahir H. Tahirov3Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical CenterEppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical CenterEppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical CenterEppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical CenterAbstract The human primosome, a four-subunit complex of DNA primase and DNA polymerase alpha (Polα), plays a critical role in DNA replication by initiating RNA and DNA synthesis on both chromosome strands. A recent study has shown that a major virulence factor in the SARS-CoV-2 infection, Nsp1 (non-structural protein 1), forms a stable complex with Polα but does not affect primosome activity. Here we show that Nsp1 inhibits DNA synthesis across inverted repeats prone to hairpin formation. Analysis of current structural data revealed the overlapping binding sites for Nsp1 and the winged helix-turn-helix domain of RPA (wHTH) on Polα, pointing to a potential competition between them. Comparison of the inhibitory effect of Nsp1 and wHTH on DNA hairpin bypass by Polα showed an eightfold lower IC50 value for Nsp1 (1 µM). This study provides valuable insight into the mechanism of inhibition of human DNA replication by Nsp1 during a SARS-CoV-2 infection.https://doi.org/10.1038/s41598-025-00982-8 |
| spellingShingle | Andrey G. Baranovskiy Lucia M. Morstadt Nigar D. Babayeva Tahir H. Tahirov Nsp1 stalls DNA polymerase α at DNA hairpins Scientific Reports |
| title | Nsp1 stalls DNA polymerase α at DNA hairpins |
| title_full | Nsp1 stalls DNA polymerase α at DNA hairpins |
| title_fullStr | Nsp1 stalls DNA polymerase α at DNA hairpins |
| title_full_unstemmed | Nsp1 stalls DNA polymerase α at DNA hairpins |
| title_short | Nsp1 stalls DNA polymerase α at DNA hairpins |
| title_sort | nsp1 stalls dna polymerase α at dna hairpins |
| url | https://doi.org/10.1038/s41598-025-00982-8 |
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