학술논문
SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence
Document Type
Article
Author
Gioia, Ubaldo; Tavella, Sara; Martínez-Orellana, Pamela; Cicio, Giada; Colliva, Andrea; Ceccon, Marta; Cabrini, Matteo; Henriques, Ana C.; Fumagalli, Valeria; Paldino, Alessia; Presot, Ettore; Rajasekharan, Sreejith; Iacomino, Nicola; Pisati, Federica; Matti, Valentina; Sepe, Sara; Conte, Matilde I.; Barozzi, Sara; Lavagnino, Zeno; Carletti, Tea; Volpe, Maria Concetta; Cavalcante, Paola; Iannacone, Matteo; Rampazzo, Chiara; Bussani, Rossana; Tripodo, Claudio; Zacchigna, Serena; Marcello, Alessandro; d’Adda di Fagagna, Fabrizio
Source
Nature Cell Biology; April 2023, Vol. 25 Issue: 4 p550-564, 15p
Subject
Language
ISSN
14657392; 14764679
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.