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dc.contributor.authorPepin, G
dc.contributor.authorNejad, C
dc.contributor.authorFerrand, J
dc.contributor.authorThomas, BJ
dc.contributor.authorStunden, HJ
dc.contributor.authorSanij, E
dc.contributor.authorFoo, C-H
dc.contributor.authorStewart, CR
dc.contributor.authorCain, JE
dc.contributor.authorBardin, PG
dc.contributor.authorWilliams, BRG
dc.contributor.authorGantier, MP
dc.date.accessioned2020-12-17T04:23:29Z
dc.date.available2020-12-17T04:23:29Z
dc.date.issued2017-09-01
dc.identifierpii: mBio.01611-17
dc.identifier.citationPepin, G., Nejad, C., Ferrand, J., Thomas, B. J., Stunden, H. J., Sanij, E., Foo, C. -H., Stewart, C. R., Cain, J. E., Bardin, P. G., Williams, B. R. G. & Gantier, M. P. (2017). Topoisomerase 1 Inhibition Promotes Cyclic GMP-AMP Synthase-Dependent Antiviral Responses. MBIO, 8 (5), https://doi.org/10.1128/mBio.01611-17.
dc.identifier.issn2150-7511
dc.identifier.urihttp://hdl.handle.net/11343/255288
dc.description.abstractInflammatory responses, while essential for pathogen clearance, can also be deleterious to the host. Chemical inhibition of topoisomerase 1 (Top1) by low-dose camptothecin (CPT) can suppress transcriptional induction of antiviral and inflammatory genes and protect animals from excessive and damaging inflammatory responses. We describe the unexpected finding that minor DNA damage from topoisomerase 1 inhibition with low-dose CPT can trigger a strong antiviral immune response through cyclic GMP-AMP synthase (cGAS) detection of cytoplasmic DNA. This argues against CPT having only anti-inflammatory activity. Furthermore, expression of the simian virus 40 (SV40) large T antigen was paramount to the proinflammatory antiviral activity of CPT, as it potentiated cytoplasmic DNA leakage and subsequent cGAS recruitment in human and mouse cell lines. This work suggests that the capacity of Top1 inhibitors to blunt inflammatory responses can be counteracted by viral oncogenes and that this should be taken into account for their therapeutic development.IMPORTANCE Recent studies suggest that low-dose DNA-damaging compounds traditionally used in cancer therapy can have opposite effects on antiviral responses, either suppressing (with the example of CPT) or potentiating (with the example of doxorubicin) them. Our work demonstrates that the minor DNA damage promoted by low-dose CPT can also trigger strong antiviral responses, dependent on the presence of viral oncogenes. Taken together, these results call for caution in the therapeutic use of low-dose chemotherapy agents to modulate antiviral responses in humans.
dc.languageEnglish
dc.publisherAMER SOC MICROBIOLOGY
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleTopoisomerase 1 Inhibition Promotes Cyclic GMP-AMP Synthase-Dependent Antiviral Responses
dc.typeJournal Article
dc.identifier.doi10.1128/mBio.01611-17
melbourne.affiliation.departmentSir Peter MacCallum Department of Oncology
melbourne.source.titlemBio
melbourne.source.volume8
melbourne.source.issue5
dc.rights.licenseCC BY
melbourne.elementsid1248604
melbourne.contributor.authorSanij, Elaine
dc.identifier.eissn2150-7511
melbourne.accessrightsOpen Access


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