In a recent review published in Mutation Research / Reviews in Mutation Research, researchers described potential coronavirus mechanisms that could cause deoxyribonucleic acid (DNA) damage and the potential link between coronavirus 2 activity (SARS-CoV- 2) Severe acute respiratory syndrome and these mechanisms.
Study: The potential role of COVID-19 in inducing DNA damage. Image credit: FOTOGRIN / Shutterstock
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Patients with coronavirus disease 2019 (COVID-19) may develop lymphopenia, elevated alanine aminotransferase and C-reactive protein (PCR) levels, and lung disorders. Long COVID-19 cases have increased and COVID-19 symptoms have been reported to occur regardless of the severity of COVID-19. SARS-CoV-2 could become endemic to humans, so understanding the long-term consequences of COVID-19 is essential.
In the present review, the researchers explored the role of SARS-CoV-2 in inducing DNA damage, which could contribute to the long-term consequences of COVID-19 in humans.
Key aspects of SARS-CoV-2 biology
SARS-CoV-2 is highly homologous to bat RaTG13 coronavirus, and the reason for its binding to the receptor (RBM) of the ear protein (S) SARS-CoV-2, which recognizes the enzyme-converting enzyme receptor human angiotensin 2 (ACE2), shares high homology with pangolin coronaviruses. This indicates that SARS-CoV-2 probably originated from recombination between pangolin coronaviruses and bats.
The SARS-CoV-2 genome consists of open reading frames 1a and 1b (ORF1a and ORF1b), which translate into two polypeptide molecules, and their cleavage results in the formation of nonstructural proteins (nsp). In addition, SARS-CoV-2 RNA serves as a template for RNA-dependent RNA polymerase (RdRp) nsp12-mediated viral replication.
SARS-CoV-2 S1 RBM binds to host ACE2, after which virion endocytosis and fusion of the SARS-CoV-2 membrane with the cell membrane occurs, releasing Intracellular SARS-CoV-2. The division of the S protein by the transmembrane protease serine 2 (TMPRSS2) facilitates endocytosis. Membrane fusion releases SARS-CoV-2 genomic RNA (gRNA) into the cytosol, facilitating SARS-CoV-2 genome replication.
Direct forms of probable coronavirus DNA damage
Related coronavirus Nsp13 such as SARS-CoV and infectious bronchitis virus (IBV) impair DNA asa polymerase activity, leading to DNA replication fork stress, damage to DNA, histones and H2AX phosphorylation (member of the H2A X histone family) and cell arrest. cycle. It is important to note that SARS-CoV nsp13 and SARS-CoV-2 are 99.8% similar, indicating that this mechanism could be similarly induced by the new SARS-CoV-2. SARS-CoV-2 infections induce overexpression of ATR (telangiectasia and Rad3-related ataxia) and CHK1 (kinase 1 control point) and telomere shortening.
The p53 tumor suppressor gene primarily regulates cell cycle, genomic stability, and inhibition of virus replication. SARS-CoV-encoded Nsp3 protein, Middle East Respiratory Syndrome coronavirus (MERS-CoV), and human coronavirus (HCoV) -NL63 promote p53 degradation and deregulation. It should be noted that nsp3 of SARS-CoV and SARS-CoV-2 is similar, the degree of deregulation of p53 could also be similar between viruses. Degradation of p53 could deregulate the APOBEC3B gene (catalytic subunit of apolipoprotein B mRNA editing enzyme 3b) and cytidine deaminase enzymes, leading to genomic instability.
The SARS-CoV (N) nucleoprotein induces overexpression of cyclooxygenase-2 (COX2) in lung cells and contributes to the transcription and binding of NF-κB (nuclear factor kappa B) and C / EBP (binding proteins). the CCAAT enhancer) COX2 promoter binding regions. COX2 enhances genetic instability and DNA damage by inducing DNA adducts and influencing cellular expression of glutathione. In addition, COX2 leads to the production of prostaglandin E2, which improves proinflammatory status and can cause exacerbations of prooxidant conditions and induce DNA damage.
Nsp1 protein can interact with subunits of the enzyme DNA polymerase α, thereby altering DNA synthesis and cell cycle regulation, and can impair DNA repair processes. In addition, it has been found that SARS-CoV-2 Nsp13 interacts with multiple centrosome proteins and alters duplication and / or centrosome structure may lead to genomic instability by facilitating anabolic pathways, leading to alterations in the structure and number of the chromosome.
Indirect forms of probable DNA damage by SARS-CoV-2
The severity of COVID-19 is characterized by overexpression of interleukin-6 (IL-6) and CRP levels. High CRP levels have been associated with increased oxidative damage to the DNA of individuals with obesity, psoriasis, obesity, cardiovascular disorders, and pancreatic cancer. Chronic and aberrant inflammation also leads to overexpression of reactive oxygen species (ROS). People with severe SARS-CoV-2 infections have a proinflammatory and prooxidative state.
In SARS-CoV-2-positive individuals, serum glutathione levels and total thiol levels are reduced. In contrast, levels of catalase superoxide dismutase (SOD) and malondialdehyde (associated with lipid peroxidation and oxidative stress) and total oxidant levels increase with a regulation or substantial increase in prooxidant gene expression, primarily calprotectin. myeloperoxidase (MPO) and genes. .
Increased levels of oxidative stress can induce various types of damage to DNA, such as breaks in single and double strands of DNA, cross-linking of DNA and proteins, and the formation of various base oxidation products. and sugars constituting nucleic acids, for example, the generation of guanine-oxidized species (GOS).
Taken together, the results highlight the potential for SARS-CoV-2 to impair DNA repair mechanisms, induce DNA damage, and induce oxidative stress in human cells, and demonstrate that COVID-19 may be a multisystemic disease that could have lasting effects on the affected organs.