How does SARS-Cov2 actually cause disease?

Excellent  review  of an important paper in Nature Cell Biology.

a paper published in Nature Cell Biology on 9 March 2023 has made what is likely to be real progress: SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence (Open Access).

Although that is a very technical title, the data are presented very clearly and completely. 

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All that is really needed to appreciate the results in this paper is some high school biology:

• According to the Central Dogma of Molecular Biology, DNA makes RNA makes protein, and that proteins are the working parts of the process and virtually all other cellular functions. DNA is a double helix of A-T and G-C base pairs.
• All cells have mechanisms to ensure that DNA damage is repaired before cell division is completed, and that when maintenance of genome integrity is disrupted normal cellular functions will fail and this failure results in disease.
• Viruses are “organisms” that replicate only when they infect host cells and viral proteins allow the virus to hijack normal cellular processes to produce new virus particles. A pathogenic virus causes disease as a consequence of its life cycle or the activity of one or more of its proteins.  Common viral diseases, historical and current, include polio, smallpox, AIDS, various conditions caused by herpes viruses, cancer (e.g., cervical and head/neck cancer caused by HPV, human papilloma virus), and COVID-19.  Virus genetic material can be RNA or DNA.

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SARS-CoV-2 infection causes DNA damage and activation of an altered DDR.  DNA damage is the consequence of the degradation of the cellular protein CHK1 by ORF6 and NSP13…Depletion of CHK1 leads to a shortage of the building blocks of DNA (the four building blocks – dNTPs – of DNA: dATP, dGTP, dCTP, dTTP; or A-T and G-C base pairs of the DNA double helix).  This deficiency results in impaired cell division, DNA damage accumulation, DDR activation, induction of inflammatory pathways and cellular senescence. Supplementation with precursors of dNTPs is sufficient to counteract this cascade of events by allowing DNA replication to proceed.  SARS-CoV-2 N-protein also interferes with DNA repair. In addition to the cultured human cells used as an experimental model, these events also occur in mice infected by SARS-CoV-2 and in patients with COVID-19.

I wonder what supplementation makes sense…