Conservation of Multifunctional Ribosomal Protein Metallopanstimulin-1 (RPS27) through Complex Evolution Demonstrates its Key Role in Growth Regulation in Archaea, Eukaryotic Cells, DNA Repair, Translation and Viral Replication

摘要

Background: When the functions of a protein serve a useful survival and unique purpose, the selective pressures of evolutionary laws of nature conserve the DNA sequences encoding such proteins. In many instances, the conservation of these sequences has occurred since the inception of life on earth to the present in phylogenetically related species. The unique function(s) of metallopanstimulin (MPS-1/RPS27) ribosomal protein (RP) and a limited number of other RPs, in growth regulation, and viral infection is further documented here. Based on the correlation of information concerning Genome Context Analysis, and new information presented here, the author proposes that neutralization or elimination of ribosomal MPS-1/S27 DNA, mRNA or translated protein in eukaryote cells, initiated in the process of chemical, viral or radiation carcinogenesis can result in control of most carcinogenic processes by selective elimination of transformed cells which display overexpression of RPMPS-1/S27, and/or non-lethal pathogenic mutations of RPMPS-1/S27 gene. Recently, critical interactions were reported between RPMPS-1/S27 and p53 induced by DNA damage such as ionizing radiation, or chemotherapy drugs, that result in the activation of p53 which in turn represses RPMPS-1/S27 actions. Thus, p53, RPS27L, and RPS27/MPS-1) regulate growth and survival. Materials and Methods: Antivirals were tested in virus-infected cells using: cell culture, cytotoxicity assays, apoptosis, defined virus strains, cloned cells, and RT-PCR. Purity of antivirals was validated by mass spectroscopy (MS). Disruption of zinc finger peptides (ZFPs), by these agents was determined by NMR. Results: The data presented here indicates that anti-ZFP agents can potentially be used to prevent and control viral infections by disrupting viral ZFP motifs. Different DNA/RNA virus-infected cells exposed to the antivirals resulted in distruption of both RPMPS-1/S27 and essential viral ZFPs. Picolinic acid (PA) and fusaric acid (FU) were tested and have been shown to have both antiviral and preventive antiviral activities which have been consistently shown to be mediated, at least in part, via interacting with RPMPS-1/S27. The same antiviral agents simultaneously disrupt essential viral ZFPs. Both antiviral events on ZFPs render the pathogenic virus inactive. Conclusion: It is demonstrated here that PA and FU exhibit antiviral activity towards several DNA and RNA viruses of human and animal importance. Illustrative evidence of the mechanism of action was obtained via MS, NMR, and molecular modeling that PA and, more potently, FU, bind to a particular site of the viral ZFPs. Similarly, it was previously shown by MS, NMR and molecular modeling with RPMPS-1/S27 that PA and FU disrupts the function of this RP protein, preventing viral replication by formation of ternary complexes. This work is consistent with a critical role of RPMPS-1/S27 in the life cycle of various viruses and shows that disruption of viral ZFPs is potentially important to control and prevent deathly viral diseases.