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

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.