Nat Cell Biol . SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence

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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 ^{# 1} , Sara Tavella ^{# 1} , Pamela Martínez-Orellana ² , Giada Cicio ^{1 3} , Andrea Colliva ² , Marta Ceccon ¹ , Matteo Cabrini ¹ , Ana C Henriques ¹ , Valeria Fumagalli ⁴ , Alessia Paldino ^{2 5} , Ettore Presot ⁶ , Sreejith Rajasekharan ^{2 7} , Nicola Iacomino ⁸ , Federica Pisati ⁹ , Valentina Matti ¹ , Sara Sepe ¹ , Matilde I Conte ¹ , Sara Barozzi ¹ , Zeno Lavagnino ¹ , Tea Carletti ² , Maria Concetta Volpe ² , Paola Cavalcante ⁸ , Matteo Iannacone ⁴ , Chiara Rampazzo ⁶ , Rossana Bussani ⁵ , Claudio Tripodo ^{1 3} , Serena Zacchigna ^{2 5} , Alessandro Marcello ² , Fabrizio d'Adda di Fagagna ^{10 11}



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.