SARS-CoV-2 hijacks host cell genome instability pathways

doi:10.21203/rs.3.rs-1556634/v1

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SARS-CoV-2 hijacks host cell genome instability pathways

https://doi.org/10.21203/rs.3.rs-1556634/v1

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posted 14 Apr, 2022

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The repertoire of coronavirus disease 2019 (COVID-19)-mediated adverse health outcomes has continued to expand in infected patients, including the susceptibility to developing long-COVID; however, the molecular underpinnings at the cellular level are poorly defined. In this study, we report that SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection triggers host cell genome instability by modulating the expression of molecules of DNA repair and mutagenic translesion synthesis. Further, SARS-CoV-2 infection causes genetic alterations, such as increased mutagenesis, telomere dysregulation, and elevated microsatellite instability (MSI). The MSI phenotype was coupled to reduced MLH1, MSH6, and MSH2 in infected cells. Strikingly, pre-treatment of cells with the REV1-targeting translesion DNA synthesis inhibitor, JH-RE-06, suppresses SARS-CoV-2 proliferation and dramatically represses the SARS-CoV-2-dependent genome instability. Mechanistically, JH-RE-06 treatment induces autophagy, which we hypothesize limits SARS-CoV-2 proliferation and, therefore, the hijacking of host-cell genome instability pathways. These results have implications for understanding the pathobiological consequences of COVID-19.

SARS-CoV-2

mutagenesis

microsatellite-instability

telomeres

REV1

autophagy

Contributions

J.V.: qPCR tests, HPRT sequencing, MSI analysis, qPCR analysis of telomeres, and patient sera. T.J.: Cellular infections, JH-RE-06 treatment of cells, RNA seq influenza, and N analysis of infected cells. E.N.L.: Western blots in hamsters, autopsy sample preparation, data analysis, and time course analysis of DDR and TLS proteins. K.E.I.: Autophagy quantification, RNA sequence, CASP9 analysis. A.M.: Resources, patient sera testing, and qPCR testing. J.J.F.: hamster infections and tissue resections. A.C. and L.P.A.: Data curation, formal analysis, DNA, and RNA isolations. J.F.: Autopsy IHC analysis. E.F. and D.M: Telomere restriction fragment analyses of Hamster DNA samples by southern blot. R.M. and J.D.: Autopsy lung patient sample preparation. N.D. and D.T.: IHC experiments on autopsy samples. W.L. and J.H.: JH-RE-06 synthesis. J.D.: RNA seq analysis. R.F.H: transdisciplinary facilitation, clinical context consultation, manuscript preparation and review. M.S.G.: MSI analysis. D.A.K.: Patient recruitment and sera isolation. P.Z.: Conceptualization and experimental design. B.t.: SARS-CoV-2 experimentation and supervision. N.C.: Conceived the project, designed experiments, resources, formal analysis, supervision, funding acquisition and wrote the manuscript with help from all authors.

Acknowledgments

We acknowledge Olivia Johnson and Cory Raymond from the Vermont Lung Center for patient recruitment and sera isolation. This work was supported in part by the University of Vermont Cancer Center summer fellowship to J.A.V., DUSRA research award to E.N.L., R00ES027028 and R35GM142982 to E.F., Confocal microscopy work was supported by NIH award number 1S10OD025030-01 from the National Center for Research Resources and the COBRE Center for Neuroscience Excellence grant (P30 RR032135 / P30 GM 103498, Imaging Core 026354), National Cancer Institute (CA191448 to P.Z. and J.H.) and the Duke Clinical and Translational Science Institute (CTSI) (UL1TR002553 to P.Z. and J.H.), University of Vermont Medical Center Foundation for clinical sample collection to D.A.K., University of Vermont Cancer Center Pilot project grant to N.C., the COBRE Pilot project grant from the Vermont Institute of Immunology and infectious diseases to N.C., and University of Vermont Office of the Vice President for Research funds to N.C., and Larner College of Medicine (LCOM) funds to N.C.

Competing interests

“P.Z. and J.H. are inventors of a patent on JH-RE-06 for cancer therapy."

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Yes there is potential Competing Interest. P.Z. and J.H. are inventors of a patent on JH-RE-06 for cancer therapy.

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