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SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence

Gioia et al., Nature Cell Biology, doi:10.1038/s41556-023-01096-x, Mar 2023
https://c19early.org/gioia.html
In vitro, animal, and ex vivo study showing that SARS-CoV-2 causes DNA damage through multiple mechanisms. Using cultured human cells (Huh7, Calu-3, and primary nasal epithelial cells), infected mice, and tissue samples from COVID-19 patients, authors found that viral proteins ORF6 and NSP13 degrade the DNA repair protein CHK1 through proteasome and autophagy pathways respectively, leading to deoxynucleoside triphosphate (dNTP) shortage, impaired DNA replication, and cellular senescence. Additionally, the viral N-protein interferes with DNA repair by competing with 53BP1 protein for damage-induced long non-coding RNAs. DNA damage was confirmed in lung tissues from infected mice and COVID-19 patients.
Gioia et al., 9 Mar 2023, peer-reviewed, 29 authors. Contact: fabrizio.dadda@ifom.eu.
Ex Vivo studies are an important part of preclinical research, however results may be very different in vivo.
SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence
Ubaldo Gioia, Sara Tavella, Pamela Martínez-Orellana, Giada Cicio, Andrea Colliva, Marta Ceccon, Matteo Cabrini, Ana C Henriques, Valeria Fumagalli, Alessia Paldino, Ettore Presot, Sreejith Rajasekharan, Nicola Iacomino, Federica Pisati, Valentina Matti, Sara Sepe, Matilde I Conte, Sara Barozzi, Zeno Lavagnino, Tea Carletti, Maria Concetta Volpe, Paola Cavalcante, Matteo Iannacone, Chiara Rampazzo, Rossana Bussani, Claudio Tripodo, Serena Zacchigna, Alessandro Marcello, Fabrizio D’adda Di Fagagna
Nature Cell Biology, doi:10.1038/s41556-023-01096-x
Gating strategy their SSC-A vs. FSC-A and SSC-A vs. SSC-H parameters. 561 nm laser and 695/40 filter were used for propidium iodide detection; 488 nm laser and 530/30 filter were used for BrdU and CHK1 detection. Tick this box to confirm that a figure exemplifying the gating strategy is provided in the Supplementary Information.
Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/ . © The Author(s) 2023 1 IFOM ETS -The AIRC Institute of Molecular Oncology, Milan, Italy. 2 International Centre for Genetic Engineering and Biotechnology, Trieste, Italy. 3 University of Palermo, Palermo, Italy. 4 IRCCS San Raffaele Scientific Institute & University, Milan, Italy. 5 University of Trieste, Trieste, Italy. 6 University of Padova, Padova, Italy. 7 Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. 8 Cogentech Società Benefit srl, Milan, Italy. 9 Institute of..
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DOI record: { "DOI": "10.1038/s41556-023-01096-x", "ISSN": [ "1465-7392", "1476-4679" ], "URL": "http://dx.doi.org/10.1038/s41556-023-01096-x", "abstract": "<jats:title>Abstract</jats:title><jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the RNA virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Although SARS-CoV-2 was reported to alter several cellular pathways, its impact on DNA integrity and the mechanisms involved remain unknown. Here we show that SARS-CoV-2 causes DNA damage and elicits an altered DNA damage response. Mechanistically, SARS-CoV-2 proteins ORF6 and NSP13 cause degradation of the DNA damage response kinase CHK1 through proteasome and autophagy, respectively. CHK1 loss leads to deoxynucleoside triphosphate (dNTP) shortage, causing impaired S-phase progression, DNA damage, pro-inflammatory pathways activation and cellular senescence. Supplementation of deoxynucleosides reduces that. Furthermore, SARS-CoV-2 N-protein impairs 53BP1 focal recruitment by interfering with damage-induced long non-coding RNAs, thus reducing DNA repair. Key observations are recapitulated in SARS-CoV-2-infected mice and patients with COVID-19. We propose that SARS-CoV-2, by boosting ribonucleoside triphosphate levels to promote its replication at the expense of dNTPs and by hijacking damage-induced long non-coding RNAs’ biology, threatens genome integrity and causes altered DNA damage response activation, induction of inflammation and cellular senescence.</jats:p>", "alternative-id": [ "1096" ], "assertion": [ { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Received", "name": "received", "order": 1, "value": "17 December 2021" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Accepted", "name": "accepted", "order": 2, "value": "25 January 2023" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "First Online", "name": "first_online", "order": 3, "value": "9 March 2023" }, { "group": { "label": "Competing interests", "name": "EthicsHeading" }, "name": "Ethics", "order": 1, "value": "M.I. participates in advisory boards/consultancies for Gilead Sciences, Roche, Third Rock Ventures, Antios Therapeutics, Asher Bio, Amgen, Allovir. 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