Identification of a Proofreading Domain within the Guanosine Diphosphate Polyribonucleotidyltransferase Domain in the Bat-borne Deadly Human Viruses: Marburg, Ebola and Nipah

The proofreading 3’→5’ exonuclease is an indispensable class of exonucleases that maintains the integrity of genomes in all organisms, from viruses to humans.  It plays a crucial role in regulating the fidelity of genome replication and its diversity. Typically, they are placed on the same polypeptide along with the DNA polymerases as a separate domain or as an associated enzyme of the replicase multienzyme complexes. In the non-segmented, positive-strand, bat-borne RNA viruses like Severe Acute/Middle East Respiratory Syndrome Coronaviruses (SARS-CoVs and MERS-CoV), it is found placed along with the methyltransferase (MTase) gene of the non-structural protein, NSP14. However, in the non-segmented, negative-strand, bat-borne RNA viruses like Marburg, Ebola and Nipah viruses, it is not found along with the MTase gene, but identified within a novel type of capping enzyme, viz. guanosine diphosphate polyribonucleotidyltransferase (PRNTase). Despite this difference in genomic organization, the proofreading exonucleases in both groups belong to the DEDD superfamily and share a conserved active site and catalytic mechanism. Specifically, they utilise a completely conserved histidine residue that functions as a proton acceptor from a metal-activated water molecule, enabling the excision of incorrectly incorporated nucleotides during genome replication. To the best of my knowledge, this study provides the first evidence for the presence of a DEDD superfamily proofreading exonuclease domain embedded within the PRNTase domain in non-segmented, negative-sense bat-borne RNA viruses such as Marburg, Ebola, and Nipah viruses.