The novel coronavirus (SARS-CoV-2), an RNA virus, is responsible for the COVID-19 pandemic. Its 30 kb genome encodes 26 polypeptides/proteins, including 16 non-structural proteins, 4 structural proteins (e.g., nucleocapsid proteins), and 6 accessory proteins.
Viral infections affect multiple cellular pathways, including autophagy, the ubiquitin-proteasome system (UPS), and the DNA damage response (DDR). Although there have been many studies on the interaction between DNA viruses and DDR, there is still a lack of specific descriptions and mechanism exploration of the effects of RNA viruses on host genome integrity and DDR.
Many studies since the COVID-19 pandemic have shown that the virus has a greater impact on human health than other respiratory viruses, and its infection can also lead to long-term COVID, which also appears to cause accelerated aging of infected people.
Nuclear DNA is the only irreplaceable cellular component, are these serious health consequences caused by the new coronavirus infection caused by its damage to the nuclear DNA?
On March 9, 2023, researchers from the AIRC Institute of Molecular Oncology in Italy published a report in Nature Cell Biology titled: SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular Senescence's research paper.
The study found that SARS-CoV-2 infection causes DNA damage both in and in vitro cultured cells. In terms of mechanism, the proteins ORF6 and NSP13 expressed by the new coronavirus cause degradation of the DNA damage reaction kinase CHK1 through proteasomes and autophagy, respectively. CHK1 deletion leads to a decrease in deoxyribonucleoside triphosphate (dNTP) for synthesizing DNA, resulting in impaired DNA replication. In addition, the new coronavirus nucleocapsid protein (N protein) inhibits 53BP1 protein recruitment by binding to damage-induced long non-coding RNA (dilncRNA), thereby reducing DNA damage repair. The appearance of DNA damage and the accumulation of repair damage lead to cellular senescence and inflammation.
That is to say, as an RNA virus, after infecting cells, its own RNA replication consumes a large amount of ribonucleoside triphosphate (rNTP), and this is at the expense of the deoxyribonucleoside triphosphate (dNTP) required for the cell's own DNA replication, in addition, the new coronavirus also hijacks damage-induced long non-coding RNA (dilncRNA) that threatens the integrity of the quality genome, activates the DNA damage response, leads to the accumulation of DNA damage, induces inflammation and cellular aging.
These findings shed light on the profound impact of coronavirus infection on cell biology, threatening the most important component of cells – nuclear DNA. DNA damage accumulation is known to be linked to cancer and aging.
To determine whether the new coronavirus infection activates the DNA damage response (DDR), the research team infected human cell lines with the new coronavirus and performed immunoblotting analysis on DDR markers. It turned out that the new coronavirus infection did activate DDR. Then, the research team used single-cell gel electrophoresis experiments to confirm the presence of DNA fragments in the cells infected with the new coronavirus. These events are accompanied by pro-inflammatory signaling and cellular senescence.
Next, the research team explored the molecular mechanism of the DNA damage response (DDR) caused by the new coronavirus infection. The research team found that the proteins expressed by the new coronavirus hijack cellular nucleotide metabolism through different mechanisms. Specifically, the viral factors ORF6 and NSP13 promote the degradation of checkpoint kinase 1 (CHK1), an enzyme involved in coordinating DDR. Decreased CHK1 levels are thought to lead to the accumulation of ribonucleoside triphosphate (rNTP), which is necessary to promote RNA virus replication, which is an RNA virus. However, the accumulation of rNTP appears to have come at the cost of reduced dNTP, which has led to a significant decrease in intracellular dNTP levels after coronavirus infection, which has led to impaired DNA replication and DNA damage.
In addition, the research team also found evidence of DNA breaks and accumulation in new coronavirus-infected cells, because the damaged DNA was not repaired in a timely and effective manner. Specifically, the competition between the nucleocapsid protein (N protein) and the 53BP1 protein of the new coronavirus binds to damage-induced long noncoding RNA, impairing the local recruitment of the binding protein 53BP1, thereby reducing DNA repair.
Overall, these findings suggest that coronavirus infection can both induce DNA damage and impair DNA damage repair, ultimately leading to cellular aging and spreading inflammation. The study also provides further evidence that these events are occurring in both mouse models and humans infected with the new coronavirus.
The dual effects of new coronavirus infection on host genome integrity and cellular senescence, left: new coronavirus infection promotes CHK1 degradation, leads to a decrease in ribonucleoside diphosphate reductase subunit (RRM2), further leads to a decrease in the level of dNTP required for DNA synthesis, inhibits DNA replication, and causes DNA damage; Right: The new coronavirus nucleocapsid protein (N protein) binds to damage-induced long non-coding RNA (dilncRNA), resulting in 53BP1 inactivation and DNA repair defects.
These findings shed light on the profound impact of coronavirus infection on cell biology, threatening the most important component of cells – nuclear DNA. DNA damage accumulation is known to be linked to cancer and aging. Although the long-term effects of coronavirus infection on the incidence of cancers such as lung cancer are not yet known, many studies have shown that it accelerates the aging phenotype.
These findings may provide a mechanistic explanation for post-COVID syndromes with accelerated aging characteristics, and the triggering of cellular aging and inflammation caused by COVID infection may be an important contributing factor. In fact, chronic inflammation is believed to be the root cause of pulmonary fibrosis, brain degeneration, and general weakness. Therefore, problems that were initially confined to the respiratory system after infection may have further systemic consequences.
Fabrizio d'Adda di Fagagna, the paper's corresponding author, said the work stemmed from a 2019 conference where he heard data — two-thirds of the transcriptomes in coronavirus-infected cells come from the virus. Here is the idea that this must have a huge impact on the availability of nucleotides that cells need to perform their normal functions. Although his laboratory does not study virus biology, his doctoral stage happens to be studying HIV, which also allows him to regain his passion for virus research. Previous studies have demonstrated the correlation between DNA damage and DNA damage response (DDR) activation and telomere-induced and oncogene-induced cellular senescence, and this study expands the correlation between DNA damage and DNA damage response (DDR) activation and virus-induced cellular senescence.
Written by | Wang Cong
Edit | King Duoyu
Typesetting | Water written
Paper Link:
https://www.nature.com/articles/s41556-023-01096-x
https://www.nature.com/articles/s41556-023-01097-w