The role of A-to-I RNA editing in infections by RNA viruses: Possible implications for SARS-CoV-2 infection

Abstract

RNA editing is a fundamental biological process with 2 major forms, namely adenosine-to-inosine (A-to-I, recognized as A-to-G) and cytosine-to-uracil (C-to-U) deamination, mediated by ADAR and APOBEC enzyme families, respectively. A-to-I RNA editing has been shown to directly affect the genome/transcriptome of RNA viruses with significant repercussions for viral protein synthesis, proliferation and infectivity, while it also affects recognition of double-stranded RNAs by cytosolic receptors controlling the host innate immune response. Recent evidence suggests that RNA editing may be present in SARS-CoV-2 genome/transcriptome. The majority of mapped mutations in SARS-CoV-2 genome are A-to-G/U-to-C(opposite strand) and C-to-U/G-to-A(opposite strand) substitutions comprising potential ADAR-/APOBEC-mediated deamination events. A single nucleotide substitution can have dramatic effects on SARS-CoV-2 infectivity as shown by the D614G(A-to-G) substitution in the spike protein. Future studies utilizing serial sampling from patients with COVID-19 are warranted to delineate whether RNA editing affects viral replication and/or the host immune response to SARS-CoV-2.

Spike Protein NTD mutation G142D in SARS-CoV-2 Delta VOC lineages is associated with frequent back mutations, increased viral loads, and immune evasion

“…The role of APOBEC and ADAR proteins in host innate immunity and their viral directed activities raises the possibility of host immunity contributing to the intra-host heterogeneity observed in the SARS-CoV-2 genome (22,(24)(25)(26). Indeed, this has been proposed as the underlying mechanism for the D614G mutation (27). Whether the observed frequent mutation and back mutation events at position 142 reported here are due to RNA editing is of interest and requires analysis beyond the scope of this study.…”

Secondary structure of subgenomic RNA M of SARS-CoV-2

“…Recently, prediction of interaction between SARS-CoV-2 genome and human proteome indicated that highly structured region at the 5′ end had the large number of interactions with proteins such as 1) ATP-dependent RNA helicase - DDX1, that was previously reported to be essential for Avian infectious bronchitis coronavirus replication [35] and 2) ADAR double-stranded RNA-specific editases, that catalyse the hydrolytic deamination of adenosine to inosine, result in affecting viral protein synthesis, proliferation and infectivity [36], and 3) 2′-5′-oligoadenylate synthetases that control viral RNA degradation [20], [37], [38]. Some of these proteins could interact with a leader sequence of sgRNA.…”

Secondary Structure of Subgenomic RNA M of SARS-CoV-2

“…SL3 is conserved only in subgroups of beta and gammaCoVs [4] and contains TRS-L sequences that take part in discontinuous transcription [11,44]. Recently, a prediction of interaction between the SARS-CoV-2 genome and the human proteome indicated that a highly structured region at the 5′ end had a large number of interactions with proteins such as (1) ATP-dependent RNA helicase-DDX1, which was previously reported to be essential for Avian infectious bronchitis coronavirus replication [18,47], (2) adenosine deaminases acting on RNA (ADAR) that catalyzes the hydrolytic Recently, a prediction of interaction between the SARS-CoV-2 genome and the human proteome indicated that a highly structured region at the 5 end had a large number of interactions with proteins such as (1) ATP-dependent RNA helicase-DDX1, which was previously reported to be essential for Avian infectious bronchitis coronavirus replication [18,47], (2) adenosine deaminases acting on RNA (ADAR) that catalyzes the hydrolytic deamination of adenosine to inosine, which affects viral protein synthesis, proliferation and infectivity [18,48], and (3) 2 -5 -oligoadenylate synthetases which control viral RNA degradation [18,49,50]. Some of these proteins could interact with a leader sequence of sgRNA.…”