SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence
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Published:2023-03-09
Issue:4
Volume:25
Page:550-564
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ISSN:1465-7392
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Container-title:Nature Cell Biology
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language:en
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Short-container-title:Nat Cell Biol
Author:
Gioia UbaldoORCID, Tavella SaraORCID, Martínez-Orellana Pamela, Cicio Giada, Colliva Andrea, Ceccon Marta, Cabrini Matteo, Henriques Ana C., Fumagalli ValeriaORCID, Paldino Alessia, Presot EttoreORCID, Rajasekharan Sreejith, Iacomino Nicola, Pisati Federica, Matti Valentina, Sepe Sara, Conte Matilde I., Barozzi Sara, Lavagnino ZenoORCID, Carletti TeaORCID, Volpe Maria Concetta, Cavalcante Paola, Iannacone MatteoORCID, Rampazzo ChiaraORCID, Bussani Rossana, Tripodo ClaudioORCID, Zacchigna SerenaORCID, Marcello AlessandroORCID, d’Adda di Fagagna FabrizioORCID
Abstract
AbstractSevere 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.
Publisher
Springer Science and Business Media LLC
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