Although SARS-CoV-2 infection has been suggested to engage components of the DDR machinery 7, 8, 9, 10, a thorough characterization and a mechanistic probing of the impact of SARS-CoV-2 on genome integrity and DDR engagement is lacking. While the interplay between some DNA viruses and DDR has been studied 5, much less is known about RNA viruses 6. Viral infections can impact on several cellular pathways, including the autophagy pathway 3, the ubiquitin–proteasome system (UPS) 4 and the DNA damage response (DDR). Its 30 kb genome encodes 26 polypeptides encompassing 16 non-structural proteins (NSPs), 4 structural proteins such as the nucleocapsid (N) protein, and 6 accessory ones 2. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an RNA virus, responsible for the ongoing coronavirus disease 2019 (COVID-19) pandemic 1. 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.
Key observations are recapitulated in SARS-CoV-2-infected mice and patients with COVID-19. Furthermore, SARS-CoV-2 N-protein impairs 53BP1 focal recruitment by interfering with damage-induced long non-coding RNAs, thus reducing DNA repair. Supplementation of deoxynucleosides reduces that. CHK1 loss leads to deoxynucleoside triphosphate (dNTP) shortage, causing impaired S-phase progression, DNA damage, pro-inflammatory pathways activation and cellular senescence. Mechanistically, SARS-CoV-2 proteins ORF6 and NSP13 cause degradation of the DNA damage response kinase CHK1 through proteasome and autophagy, respectively. Here we show that SARS-CoV-2 causes DNA damage and elicits an altered DNA damage response. Although SARS-CoV-2 was reported to alter several cellular pathways, its impact on DNA integrity and the mechanisms involved remain unknown. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the RNA virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Nature Cell Biology volume 25, pages 550–564 ( 2023) Cite this article SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence
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