SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence
- Autori: Gioia U.; Tavella S.; Martinez-Orellana P.; Cicio G.; Colliva A.; Ceccon M.; Cabrini M.; Henriques A.C.; Fumagalli V.; Paldino A.; Presot E.; Rajasekharan S.; Iacomino N.; Pisati F.; Matti V.; Sepe S.; Conte M.I.; Barozzi S.; Lavagnino Z.; Carletti T.; Volpe M.C.; Cavalcante P.; Iannacone M.; Rampazzo C.; Bussani R.; Tripodo C.; Zacchigna S.; Marcello A.; d'Adda di Fagagna F.
- Anno di pubblicazione: 2023
- Tipologia: Articolo in rivista
- OA Link: http://hdl.handle.net/10447/584373
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.