Colorized scanning electron micrograph of a cell (red) heavily infected with SARS-CoV-2 virus particles (green), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID/NIH.
DNA damage could be the main factor behind the effects of infection with Sars-CoV-2 virus, according to a study1 led by Fabrizio d’Adda di Fagagna from IFOM, in Milan. The research team, including members from CNR-IGM in Pavia and ICGEB in Trieste, identified the molecular basis of the cellular aggression of the virus, and found that it can damage DNA, and halt its repair, causing cellular senescence and chronic inflammation.
Cellular senescence is a break in the cell cycle that can be triggered in response to internal and external stress. “We previously showed that the accumulation of DNA damage leads to senescence, that regulates cell fate and is associated with ageing and cancer,” explains d’Adda di Fagagna2. In particular, the group found that the senescence-associated secretory phenotype (SASP) is associated with cells which secrete high levels of inflammatory and cytokines production. Basically, senescence has the double role of stopping cells from proliferating, and allowing inflammation.
Other groups have recently shown3 that viruses could induce senescence, but nobody had investigated the correlation between DNA damage and the effects of Sars-CoV-2. By looking at the sequencing data from infected cells with Sars-CoV-2, D’Adda di Fagagna noticed that most of it was viral RNA, and wondered whether the virus was having an impact on DNA damage. The intuition was right. “The virus breaks the DNA and prevents its repair, inducing the cell in a state of senescence and making it spit out cytokines”.
Using different in vitro cellular systems, the researchers discovered that Sars-CoV-2 enters the cell and forces it to give out ribonucleoside triphosphate (rNTP), the material to synthesize its RNA. This in turn results in a reduction of the cellular levels of deoxynucleoside triphosphated (dNTPs), the building block of DNA.
In parallel, the scientists observed, DNA damage accumulates in the cell, because certain proteins of the virus interfere with the cellular repair mechanisms by impairing 53BP1, a a binding protein necessary for repairing DNA lesions. This causes cellular senescence and the production of inflammatory cytokines.
The ‘cytokine storm’ that is typical of severe COVID-19 cases could be caused not only by immune cells, but also by cells in senescence, the researchers suggest. The data were also confirmed in vivo, both in mouse model systems of infection and in post- mortem tissues of patients with COVID-19.
“We would like to better understand the contribution of the different variants,” concludes d’Adda di Fagagna. “On a more cellular level, we aim to figure out where exactly the DNA damage occurs to better understand its impact”.
