Role of RNA modifications in coronaviruses replication

National Institute Of Environmental Health Sciences

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Abstract

SARS-CoV-2, the virus responsible for the current pandemic, belongs to the coronavirus family. These viruses have a polyadenylated RNA genome that replicates within the infected cells. The poly(A) tail of the virus is critical for viral RNA integrity and changes in length during the course of the infection. However, the molecular pathways controlling viral RNA synthesis and processing are poorly understood. Coronaviruses encode for several RNA processing enzymes, but they also depend on host proteins for their replication. We hypothesize that some host RNA binding proteins previously implicated in poly(A) processing of other viruses might contribute to the metabolism of coronaviruses' RNA. During this year, we used established cell lines lacking endogenous RNA binding proteins and a state-of-the-art sequencing protocol to define the role of endogenous proteins in viral RNA processing and replication. We observed that the endogenous enzymes TUT4 and TUT7 directly target the poly(A) tail of the viral RNA. Depleting TUT4 and TUT7 results in an increase in the viral RNA load affecting the viral replication dynamics. By measuring the virus poly(A) tail length and RNA modifications in infected cells depleted of key RNA regulatory proteins, we were able to provide insights into molecular pathways controlling coronavirus replication.