tetano
Editor, Senior Moderator
Nat Cell Biol
. 2023 Mar 9.
doi: 10.1038/s41556-023-01096-x. Online ahead of print.
SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence
Ubaldo Gioia[SUP] #[/SUP][SUP] 1 [/SUP], Sara Tavella[SUP] #[/SUP][SUP] 1 [/SUP], Pamela Martínez-Orellana[SUP] 2 [/SUP], Giada Cicio[SUP] 1 3 [/SUP], Andrea Colliva[SUP] 2 [/SUP], Marta Ceccon[SUP] 1 [/SUP], Matteo Cabrini[SUP] 1 [/SUP], Ana C Henriques[SUP] 1 [/SUP], Valeria Fumagalli[SUP] 4 [/SUP], Alessia Paldino[SUP] 2 5 [/SUP], Ettore Presot[SUP] 6 [/SUP], Sreejith Rajasekharan[SUP] 2 7 [/SUP], Nicola Iacomino[SUP] 8 [/SUP], Federica Pisati[SUP] 9 [/SUP], Valentina Matti[SUP] 1 [/SUP], Sara Sepe[SUP] 1 [/SUP], Matilde I Conte[SUP] 1 [/SUP], Sara Barozzi[SUP] 1 [/SUP], Zeno Lavagnino[SUP] 1 [/SUP], Tea Carletti[SUP] 2 [/SUP], Maria Concetta Volpe[SUP] 2 [/SUP], Paola Cavalcante[SUP] 8 [/SUP], Matteo Iannacone[SUP] 4 [/SUP], Chiara Rampazzo[SUP] 6 [/SUP], Rossana Bussani[SUP] 5 [/SUP], Claudio Tripodo[SUP] 1 3 [/SUP], Serena Zacchigna[SUP] 2 5 [/SUP], Alessandro Marcello[SUP] 2 [/SUP], Fabrizio d'Adda di Fagagna[SUP] 10 11 [/SUP]
Affiliations
Abstract
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.
. 2023 Mar 9.
doi: 10.1038/s41556-023-01096-x. Online ahead of print.
SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence
Ubaldo Gioia[SUP] #[/SUP][SUP] 1 [/SUP], Sara Tavella[SUP] #[/SUP][SUP] 1 [/SUP], Pamela Martínez-Orellana[SUP] 2 [/SUP], Giada Cicio[SUP] 1 3 [/SUP], Andrea Colliva[SUP] 2 [/SUP], Marta Ceccon[SUP] 1 [/SUP], Matteo Cabrini[SUP] 1 [/SUP], Ana C Henriques[SUP] 1 [/SUP], Valeria Fumagalli[SUP] 4 [/SUP], Alessia Paldino[SUP] 2 5 [/SUP], Ettore Presot[SUP] 6 [/SUP], Sreejith Rajasekharan[SUP] 2 7 [/SUP], Nicola Iacomino[SUP] 8 [/SUP], Federica Pisati[SUP] 9 [/SUP], Valentina Matti[SUP] 1 [/SUP], Sara Sepe[SUP] 1 [/SUP], Matilde I Conte[SUP] 1 [/SUP], Sara Barozzi[SUP] 1 [/SUP], Zeno Lavagnino[SUP] 1 [/SUP], Tea Carletti[SUP] 2 [/SUP], Maria Concetta Volpe[SUP] 2 [/SUP], Paola Cavalcante[SUP] 8 [/SUP], Matteo Iannacone[SUP] 4 [/SUP], Chiara Rampazzo[SUP] 6 [/SUP], Rossana Bussani[SUP] 5 [/SUP], Claudio Tripodo[SUP] 1 3 [/SUP], Serena Zacchigna[SUP] 2 5 [/SUP], Alessandro Marcello[SUP] 2 [/SUP], Fabrizio d'Adda di Fagagna[SUP] 10 11 [/SUP]
Affiliations
- PMID: 36894671
- DOI: 10.1038/s41556-023-01096-x
Abstract
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.