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.

严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 是导致 2019 年冠状病毒病 (COVID-19) 大流行的 RNA 病毒。尽管据报道 SARS-CoV-2 会改变多种细胞通路，但其对 DNA 完整性的影响以及所涉及的机制仍然未知。在这里，我们证明 SARS-CoV-2 会引起 DNA 损伤并引发 DNA 损伤反应的改变。从机制上讲，SARS-CoV-2 蛋白 ORF6 和 NSP13 分别通过蛋白酶体和自噬导致 DNA 损伤反应激酶 CHK1 降解。 CHK1 缺失会导致脱氧核苷三磷酸 (dNTP) 短缺，从而导致 S 期进展受损、DNA 损伤、促炎途径激活和细胞衰老。补充脱氧核苷可以减少这种情况。此外，SARS-CoV-2 N 蛋白通过干扰损伤诱导的长非编码 RNA 来损害 53BP1 焦点募集，从而减少 DNA 修复。在感染 SARS-CoV-2 的小鼠和患有 COVID-19 的患者中重述了主要观察结果。我们认为，SARS-CoV-2 通过提高核糖核苷三磷酸水平以牺牲 dNTP 为代价促进其复制，并劫持损伤诱导的长非编码 RNA 的生物学特性，威胁基因组完整性并导致改变 DNA 损伤反应激活、诱导炎症和细胞衰老。