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The roles of APOBEC-mediated RNA editing in SARS-CoV-2 mutations, replication and fitness
Open accessPublished version of a preprint
Abstract
During COVID-19 pandemic, mutations of SARS-CoV-2 produce new strains that can be more infectious or evade vaccines. Viral RNA mutations can arise from misincorporation by RNA-polymerases and modification by host factors. Analysis of SARS-CoV-2 sequence from patients showed a strong bias toward C-to-U mutation, suggesting a potential mutational role by host APOBEC cytosine deaminases that possess broad anti-viral activity. We report the first experimental evidence demonstrating that APOBEC3A, APOBEC1, and APOBEC3G can edit on specific sites of SARS-CoV-2 RNA to produce C-to-U mutations. However, SARS-CoV-2 replication and viral progeny production in Caco-2 cells are not inhibited by the expression of these APOBECs. Instead, expression of wild-type APOBEC3 greatly promotes viral replication/propagation, suggesting that SARS-CoV-2 utilizes the APOBEC-mediated mutations for fitness and evolution. Unlike the random mutations, this study suggests the predictability of all possible viral genome mutations by these APOBECs based on the UC/AC motifs and the viral genomic RNA structure.
Overview
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Written from the paper’s full text.
TL;DR
This study provides experimental evidence that APOBEC3A, APOBEC1 plus A1CF, and APOBEC3G can directly edit specific SARS-CoV-2 RNA sites to cause C-to-U mutations. Rather than inhibiting SARS-CoV-2, wild-type APOBEC3A expression promoted viral RNA replication and progeny production in Caco-2 cells, suggesting the virus can use APOBEC-mediated mutations for fitness and evolution.
Key findings
- Among 307 total C sites in seven selected viral RNA segments, significant C-to-U editing sites numbered 135 for A1 + A1CF, 67 for A3A, and 11 for A3G; editing efficiencies reached as high as 22.2% for A1 + A1CF, 4.5% for A3A, and 0.18% for A3G.
- A3A preferred a UC motif and A1 + A1CF preferred an AC motif; among C-to-U variations analyzed, AC-to-AU accounted for 38.23% and UC-to-UU for 31.83%, versus 15.44% for GC-to-GU and 14.50% for CC-to-CU.
- In Caco-2 cells, A1 + A1CF or A3G expression did not significantly change viral RNA levels up to 96 h post-infection, but A3A expression significantly increased viral RNA at 72 and 96 h and produced approximately 10–100-fold higher viral progeny at 72 h.
- Database analysis found C-to-U was the predominant mutation in the 5′UTR-Orf1a region, accounting for ~55.8% of single nucleotide variants; the A3A-edited UC241 mutation became a signature of dominant strains, with 90% of circulating variants carrying it by July 2020 and almost all by March 2021.
Methods
- Cell-based RNA editing assay: seven 200 nt SARS-CoV-2 RNA segments were inserted into reporter vectors, co-transfected with APOBEC editor vectors (A1 + A1CF, A3A, or A3G) in HEK293T cells, and analyzed by Safe-Sequencing-System (SSS) deep sequencing with UID barcodes to distinguish true editing from PCR/sequencing errors.
- Infection experiments: Caco-2 stable cell lines expressing A1 + A1CF, A3A, or A3G under a tetracycline-controlled promoter were infected with SARS-CoV-2 (MOI = 0.05); viral RNA replication was measured by qPCR for Nsp12, S, and N regions, and progeny yield by plaque assay on Vero E6 cells.
- Sequence analysis: publicly available SARS-CoV-2 genome data from Nextstrain/GISAID (Dec. 2019 to Jan. 22, 2022) were analyzed for mutational events and C-to-U prevalence.
Limitations
- The paper states that SSS sequencing is several times more expensive than regular NGS, each read covers ~150–200 nt, and it was too expensive to cover the entire ~30,000 nt SARS-CoV-2 genome, so only seven viral RNA segments were selected.
- The paper states that A3G edited only a small number of sites (n = 11) and did not show a clear motif preference, so more SARS-CoV-2 regions and/or folded RNA structures are needed to verify A3G-mediated editing; UC/AC motifs alone are insufficient for efficient editing, and the exact RNA structural features remain to be defined.
- The paper notes that a minor deaminase-independent enhancement by inactive A3A-E72A was observed and warrants further validation, and that host RNA or DNA editing by WT A3A could also contribute to increased viral replication/progeny; it also states that multiple viral passages in cell culture or animal models are needed to better assess mutation effects on fitness.
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Claims the paper makes
20 of 79 cited sources checked · 9 supported · 0 flagged · accuracy not yet measured
- Findingown data
Even the very recent omicron variants, which began to spread from Nov. 2021 rapidly, continue to show noticeable C-to-U editing pattern.
“Even the very recent omicron variants, which began to spread from Nov. 2021 rapidly, continue to show noticeable C-to-U editing pattern (Supplementary Fig. S7B).”
Quote in the paperSubstantial claim - Findingown data
Expression of wild-type APOBEC3 greatly promotes viral replication/propagation.
“Instead, expression of wild-type APOBEC3 greatly promotes viral replication/propagation, suggesting that SARS-CoV-2 utilizes the APOBEC-mediated mutations for fitness and evolution.”
Quote in the paperSubstantial claim - Findingown data
The virus titer from the cell line expressing A3A consistently showed an approximately 10-100 fold higher than the control and A1 + A1CF and A3G expressing cell lines at 72 h.
“the virus titer from the cell line expressing A3A consistently showed an approximately 10–100 fold higher than the control and A1 + A1CF and A3G expressing cell lines at 72 h (Fig. 5C).”
Quote in the paperSubstantial claim - Findingown data
A3A expression in the stable Caco-2 cell line correlates with significantly higher viral progeny yield after 3 days of infection.
“Consistent with the increased viral RNA replication, A3A expression in the stable Caco-2 cell line also correlates with significantly higher viral progeny yield after 3 days of infection.”
Quote in the paperSubstantial claim - Findingown data
The AC to AU mutation at C23525 resulted in an H655Y mutation on the spike protein.
“Notably, the AC to AU mutation at C23525 resulted an H655Y mutation on the spike protein (Supplementary Fig. S7B), and the H655Y mutation was shown to alter cell entry pathways, i.e. the mutation is responsible for the preferential usage of endosomal pathway over cell surface entry pathways41.”
Quote in the paperSubstantial claim
- Findingown data
The preferred motif by A3G is not a clear cut from our data, possibly due to the low activity on the limited number of edited sites among the seven tested viral segments.
“However, the preferred motif by A3G is not a clear cut from our data, possibly due to the low activity on the limited number of edited sites among the seven tested viral segments.”
Quote in the paperNot a substantial claim - Findingown data
The top 3 highest A3A-mediated editing sites on SARS-CoV-2 RNA reported here all have the UC motifs in the loop of a predicted stem-loop secondary structure.
“Interestingly, our top 3 highest A3A-mediated editing sites on SARS-CoV-2 RNA reported here all have the UC motifs in the loop of a predicted stem-loop secondary structure (Fig. 3B).”
Quote in the paperNot a substantial claim - Findingown data
SARS-CoV-2 replication and viral progeny production in Caco-2 cells are not inhibited by the expression of these APOBECs.
“However, SARS-CoV-2 replication and viral progeny production in Caco-2 cells are not inhibited by the expression of these APOBECs.”
Quote in the paperSubstantial claim - Findingown data
No difference in viral titer was observed at 48 h from all cell lines with or without APOBEC expression.
“While no difference in viral titer was observed at 48 h from all cell lines with or without APOBEC expression, the virus titer from the cell line expressing A3A consistently showed an approximately 10–100 fold higher than the control and A1 + A1CF and A3G expressing cell lines at 72 h (Fig. 5C).”
Quote in the paperNot a substantial claim - Findingown data
APOBEC3A, APOBEC1, and APOBEC3G can edit specific sites of SARS-CoV-2 RNA to produce C-to-U mutations.
“We report the first experimental evidence demonstrating that APOBEC3A, APOBEC1, and APOBEC3G can edit on specific sites of SARS-CoV-2 RNA to produce C-to-U mutations.”
Quote in the paperSubstantial claim - Findingown data
The sequence context near the unedited C sites by the corresponding APOBECs also shows no particular trend except for a relatively small ratios change of the − 1 position.
“The sequence context near the unedited C sites by the corresponding APOBECs also shows no particular trend except for a relatively small ratios change of the − 1 position (e.g., less A by A1 + A1CF and less U by A3A, respectively) (Supplementary Fig. S3B–D).”
Quote in the paperNot a substantial claim - Findingown data
Caco-2 cell lines have no detectible endogenous expression of A1, A3A, and A3G protein.
“Because Caco-2 cell lines have no detectible endogenous expression of A1, A3A, and A3G protein (Supplementary Fig. S8), we first constructed Caco-2 stable cell lines expressing one of the three APOBEC genes.”
Quote in the paperSubstantial claim - Findingown data
The editing efficiency at C16063 (4.5%) is about threefold higher than the third efficiently edited site at C23453 (1.6%).
“Again, the editing efficiency at C16063 (4.5%) is about threefold higher than the third efficiently edited site at C23453 (1.6%) (Fig. 3B).”
Quote in the paperNot a substantial claim - Findingown data
Each of the three APOBEC proteins showed a strong preference for specific dinucleotide sequence motifs (i.e. AC, UC, or CC sequence motifs) for editing on the viral RNA.
“Although each of the three APOBEC proteins showed a strong preference for specific dinucleotide sequence motifs (i.e. AC, UC, or CC sequence motifs) for editing on the viral RNA, the relative editing efficiency of these motif sites vary greatly, such as between 0.0041 and 22.15% for A1 + A1CF, and between 0.0040 and 4.46% for A3A (Supplementary Dataset File 2).”
Quote in the paperNot a substantial claim - Findingown data
The sequence context near all C sites (edited + unedited sites) in the selected viral region does not show a specific feature.
“As a control, the sequence context near all C sites (edited + unedited sites) in the selected viral region does not show a specific feature (Supplementary Fig. S3A).”
Quote in the paperNot a substantial claim - Findingown data
C-to-U is the predominant mutation for the entire genome, accounting for ~ 55.8% among all single nucleotide variants (SNVs) within the SARS-CoV-2 5′UTR-Orf1a region (142-341 nt).
“The analysis revealed that the C-to-U is the predominant mutation for the entire genome, accounting for ~ 55.8% among all single nucleotide variants (SNVs) within the SARS-CoV-2 5′UTR-Orf1a region (142–341 nt, the segment tested in our reporter 1 vector) (Fig. 4A and Supplementary Fig. S6A).”
Quote in the paperSubstantial claim - Findingown data
The abundance of viral RNAs has increased significantly in the cell lines expressing A3A at 72 h and 96 h post SARS-CoV-2 infection.
“Unexpectedly, the abundance of viral RNAs has increased significantly in the cell lines expressing A3A at 72 h and 96 h post SARS-CoV-2 infection.”
Quote in the paperSubstantial claim - Findingown data
Analysis of the top 3 sites edited by A3G also showed the CC (or UC) motifs in the single-stranded loop region of a predicted stem-loop secondary structure.
“Analysis of the top 3 sites edited by A3G also showed the CC (or UC) motifs in the single-stranded loop region of a predicted stem-loop secondary structure (Fig. 3C).”
Quote in the paperNot a substantial claim - Findingown data
In all representative clades of SARS-CoV-2 emerged over the last two years since the initial outbreak, the C-to-U mutations have been much more pronounced than other types of single nucleotide variations.
“In all representative clades of SARS-CoV-2 emerged over the last two years since the initial outbreak, the C-to-U mutations have been much more pronounced than other types of single nucleotide variations (Supplementary Fig. S7A).”
Quote in the paperSubstantial claim - Findingown data
Compared with the control Caco-2 cell line, no significant change of viral RNA level was detected by qPCR with the cell lines expressing A1 + A1CF or A3G even up to 96 h post-infection.
“The replication assay results showed that, compared with the control Caco-2 cell line, no significant change of viral RNA level was detected by qPCR with the cell lines expressing A1 + A1CF or A3G even up to 96 h post-infection (Fig. 5B).”
Quote in the paperSubstantial claim - Findingown data
The UC and AC motifs alone are not sufficient for efficient editing by A3A or A1 + A1CF.
“However, the UC and AC motifs alone are not sufficient for efficient editing by A3A or A1 + A1CF.”
Quote in the paperSubstantial claim - Findingown data
Many UC and AC motifs in the SARS-CoV-2 RNA showed only the background level of C-to-U mutation.
“Many of the UC and AC motifs in the SARS-CoV-2 RNA showed only the background level of C-to-U mutation (Supplementary Dataset File 2), which suggest that additional RNA structural features around the UC/AC motifs should play an important role in dictating whether a UC or AC site can be efficiently edited (Fig. 3).”
Quote in the paperSubstantial claim - Findingown data
A3G editing rate reached as high as 0.18% at specific viral RNA sites on selected viral RNA transcript populations.
“Our results demonstrated that the three tested APOBECs show different editing rate at specific viral RNA sites, reaching as high as 22.2% for A1 + A1CF, 4.5% for A3A, and 0.18% for A3G, respectively, on the selected viral RNA transcript populations (Fig. 2).”
Quote in the paperNot a substantial claim - Findingown data
Expression of WT A3A in the tested cells showed significant increases of viral RNA replication and viral progeny production after 72 h postinfection.
“Surprisingly, expression of WT A3A in the tested cells showed significant increases of the viral RNA replication and the viral progeny production after 72 h postinfection (Fig. 5B,C, Supplementary Fig. S10), even though some increase of replication and progeny production was also observed in the inactive-A3A mutant expressing cell line (Supplementary Fig. S10).”
Quote in the paperSubstantial claim - Findingown data
A3A editing rate reached as high as 4.5% at specific viral RNA sites on selected viral RNA transcript populations.
“Our results demonstrated that the three tested APOBECs show different editing rate at specific viral RNA sites, reaching as high as 22.2% for A1 + A1CF, 4.5% for A3A, and 0.18% for A3G, respectively, on the selected viral RNA transcript populations (Fig. 2).”
Quote in the paperSubstantial claim - Findingown data
The nearby C203 and C222, where C203U and C222U mutations displayed a neutral effect on viral replication, showed a slight but statistically non-significant increase in C to U mutations 72 h post viral infection in WT A3A overexpression.
“Contrary to the editing at C241, our sequencing results showed that the nearby C203 and C222, where C203U and C222U mutations displayed a neutral effect on viral replication, showed a slight but statistically non-significant increase in C to U mutations 72 h post viral infection in WT A3A overexpression (Supplementary Fig. S11B).”
Quote in the paperNot a substantial claim - Findingown data
A1 + A1CF editing rate reached as high as 22.2% at specific viral RNA sites on selected viral RNA transcript populations.
“Our results demonstrated that the three tested APOBECs show different editing rate at specific viral RNA sites, reaching as high as 22.2% for A1 + A1CF, 4.5% for A3A, and 0.18% for A3G, respectively, on the selected viral RNA transcript populations (Fig. 2).”
Quote in the paperSubstantial claim - Findingown data
AC-to-AU mutations were not detected in A1 alone.
“Because the AC-to-AU mutations was not detected in A1 alone (Supplementary Fig. S5), it indicates that the AC-to-AU editing also requires a cofactor A1CF.”
Quote in the paperSubstantial claim - Findingown data
A3G edits a small number (n = 11) of SARS-CoV-2 RNA sites in this study.
“A3G edits a small number (n = 11) of SARS-CoV-2 RNA in our study (Fig. 2).”
Quote in the paperNot a substantial claim - Findingown data
This significant C241U mutation correlates with the time points (72 and 96 h) with detectible increases in viral RNA replication and viral progeny production.
“This significant C241U mutation correlates with the time points (72 and 96 h) with detectible increases in viral RNA replication and viral progeny production.”
Quote in the paperSubstantial claim - Findingown data
Among many detected A3A edited sites on SARS-CoV-2 RNA in our study are three C-to-U mutations located in the 5'UTR region, UC203, UC222, UC241.
“Among many of the detected A3A edited sites on SARS-CoV-2 RNA in our study are three C-to-U mutations located in the 5’UTR region, UC203, UC222, UC241 (Fig. 4A,B).”
Quote in the paperSubstantial claim - Findingown data
SARS-CoV-2 from patients detected all three mutations (UC203, UC222, UC241) at different stages since early 2020.
“The SARS-CoV-2 from patients detected all of these three mutations at different stages since early 2020, but only major circulating viral strains since early 2020 acquired the mutation at UC241 (Fig. 4C, Supplementary Fig. S6C), suggesting that C-to-U mutation at UC241 is selected for better viral fitness.”
Quote in the paperSubstantial claim - Findingcitation
The editing efficiency at a specific site is a few orders of magnitude higher than the estimated ~10^-6-10^-7 random incorporation error rate for coronavirus replication.
“This editing efficiency at a specific site is a few orders of magnitude higher compared with the estimated ~ 10–6–10–7 random incorporation error rate for Coronaviruses replication53.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [53] Smith, E. C., Sexton, N. R. & Denison, M. R. Thinking outside the triangle: Replication fidelity of the largest RNA viruses. Annu. Rev. Virol. 1, 111–132. https://doi.org/10.1146/annurev-virology-031413-085507 (2014). source
- Findingown data
In our experimental system, the editing efficiency of A1 + A1CF on the AC motif is much higher than A3A on the UC motif.
“In our experimental system, the editing efficiency of A1 + A1CF on the AC motif is much higher than A3A on the UC motif (Fig. 2C,D).”
Quote in the paperSubstantial claim - Findingown data
Analysis of SARS-CoV-2 variants from the database showed higher AC motif mutations (38.3%) than UC motif mutations (31.2%).
“Interestingly, analysis of SARS-CoV-2 variants from the database also showed higher AC motif mutations (38.3%) than UC motif mutations (31.2%) (Supplementary Fig. S4), as also reported in the previous bioinformatic database analysis3,11,27.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [3] Kockler, Z. W. & Gordenin, D. A. From RNA world to SARS-CoV-2: The edited story of RNA viral evolution. Cells https://doi.org/10.3390/cells10061557 (2021). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [11] Di Giorgio, S., Martignano, F., Torcia, M. G., Mattiuz, G. & Conticello, S. G. Evidence for host-dependent RNA editing in the transcriptome of SARS-CoV-2. Sci. Adv. 6, eabb5813. https://doi.org/10.1126/sciadv.abb5813 (2020). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [27] Klimczak, L. J., Randall, T. A., Saini, N., Li, J. L. & Gordenin, D. A. Similarity between mutation spectra in hypermutated genomes of rubella virus and in SARS-CoV-2 genomes accumulated during the COVID-19 pandemic. PLoS One 15, e0237689. https://doi.org/10.1371/journal.pone.0237689 (2020). source
Checked before — its earlier verdict is held back until a new check runs.
- Findingown data
Some increase of replication and progeny production was also observed in the inactive-A3A mutant expressing cell line.
“Surprisingly, expression of WT A3A in the tested cells showed significant increases of the viral RNA replication and the viral progeny production after 72 h postinfection (Fig. 5B,C, Supplementary Fig. S10), even though some increase of replication and progeny production was also observed in the inactive-A3A mutant expressing cell line (Supplementary Fig. S10).”
Quote in the paperNot a substantial claim - Findingown data
A1 plus its cofactor A1CF can efficiently edit specific AC motif sites of SARS-CoV-2 viral RNA.
“The data here demonstrate that A1 plus its cofactor A1CF can efficiently edit specific AC motif sties of the viral RNA (Figs. 2, 3).”
Quote in the paperSubstantial claim - Findingown data
Certain sites of SARS-CoV-2 genomic RNA can be directly edited with high efficiency by A3A and A1 + A1CF to cause C-to-U mutation.
“In summary, we report here the experimental evidence demonstrating that certain sites of SARS-CoV-2 genomic RNA can be directly edited with high efficiency by A3A and A1 + A1CF to cause C-to-U mutation.”
Quote in the paperSubstantial claim - Findingown data
Only major circulating viral strains since early 2020 acquired the mutation at UC241.
“The SARS-CoV-2 from patients detected all of these three mutations at different stages since early 2020, but only major circulating viral strains since early 2020 acquired the mutation at UC241 (Fig. 4C, Supplementary Fig. S6C), suggesting that C-to-U mutation at UC241 is selected for better viral fitness.”
Quote in the paperSubstantial claim - Findingown data
The C241 started to show clearly detectible (and statistically significant) C-to-U mutation 72 and 96 h post infection in Caco-2 cells with WT A3A.
“The results demonstrated that the C241 started to show clearly detectible (and statistically significant) C-to-U mutation 72 and 96 h post infection in Caco-2 cells with WT A3A (Supplementary Fig. S11A,B).”
Quote in the paperSubstantial claim - Findingown data
RNA editing of SARS-CoV-2 by A3A can promote viral replication/propagation.
“Even though some APOBECs, including A3A, are regarded as host antiviral factors, we show here that RNA editing of SARS-CoV-2 by A3A can promote viral replication/propagation.”
Quote in the paperSubstantial claim - Findingown data
The three tested APOBECs show different editing rates at specific viral RNA sites.
“Our results demonstrated that the three tested APOBECs show different editing rate at specific viral RNA sites, reaching as high as 22.2% for A1 + A1CF, 4.5% for A3A, and 0.18% for A3G, respectively, on the selected viral RNA transcript populations (Fig. 2).”
Quote in the paperSubstantial claim - Premisecitation
The H655Y mutation was shown to alter cell entry pathways, i.e. the mutation is responsible for the preferential usage of endosomal pathway over cell surface entry pathways.
“and the H655Y mutation was shown to alter cell entry pathways, i.e. the mutation is responsible for the preferential usage of endosomal pathway over cell surface entry pathways41.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [41] Yamamoto, M. et al. SARS-CoV-2 Omicron spike H655Y mutation is responsible for enhancement of the endosomal entry pathway and reduction of cell surface entry pathways. BioRxiv https://doi.org/10.1101/2022.03.21.485084 (2022). source
Checked before — its earlier verdict is held back until a new check runs.
- Interpretationown data
SARS-CoV-2 utilizes the APOBEC-mediated mutations for fitness and evolution.
“suggesting that SARS-CoV-2 utilizes the APOBEC-mediated mutations for fitness and evolution.”
Quote in the paperSubstantial claim - Interpretationown data
Presence of A3A expression appears to endow an advantage for the viral RNA replication.
“These results suggest that, despite the general viral restriction function of APOBECs, presence of A3A expression appears to endow an advantage for the viral RNA replication.”
Quote in the paperSubstantial claim - Premisecitation
Three APOBECs, APOBEC1 (A1), APOBEC3A (A3A), and APOBEC3G (A3G), are shown to deaminate certain cellular single-stranded RNA targets to cause C-to-U editing.
“While most APOBECs use single-stranded DNA (ssDNA) as substrate for C-deamination (reviewed in Ref.19), three APOBECs, APOBEC1 (A1)23,24, APOBEC3A (A3A)25, and APOBEC3G (A3G)26, are also shown to deaminate certain cellular single-stranded RNA (ssRNA) targets to cause C-to-U editing.”
- Also stated in: § APOBEC-mediated editing test of SARS-CoV-2 RNA · plain
“Because A1 + A1CF (APOBEC1 Complementation Factor), A3A, and A3G are the three APOBEC proteins shown to possess RNA editing activities24–26, we tested each of these three APOBEC proteins for their ability to edit SARS-CoV-2 RNA.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [23] Driscoll, D. M., Wynne, J. K., Wallis, S. C. & Scott, J. An in vitro system for the editing of apolipoprotein B mRNA. Cell 58, 519–525. https://doi.org/10.1016/0092-8674(89)90432-7 (1989). source
- cites [24] Teng, B., Burant, C. F. & Davidson, N. O. Molecular cloning of an apolipoprotein B messenger RNA editing protein. Science 260, 1816–1819. https://doi.org/10.1126/science.8511591 (1993). source
- cites [25] Sharma, S. et al. APOBEC3A cytidine deaminase induces RNA editing in monocytes and macrophages. Nat. Commun. 6, 6881. https://doi.org/10.1038/ncomms7881 (2015). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [26] Sharma, S., Patnaik, S. K., Taggart, R. T. & Baysal, B. E. The double-domain cytidine deaminase APOBEC3G is a cellular site-specific RNA editing enzyme. Sci. Rep. 6, 39100. https://doi.org/10.1038/srep39100 (2016). source
Checked before — its earlier verdict is held back until a new check runs.
- Also stated in: § APOBEC-mediated editing test of SARS-CoV-2 RNA · plain
- Interpretationnone given
All possible viral genome mutations by these APOBECs can be predicted based on the UC/AC motifs and the viral genomic RNA structure.
“this study suggests the predictability of all possible viral genome mutations by these APOBECs based on the UC/AC motifs and the viral genomic RNA structure.”
Quote in the paperSubstantial claim - Study design and conductreasoning
The probability that three out of three reads will all have the same sequencing error at a site is 10^-7.
“The probability that three out of three reads will all have the same sequencing error at a site is then 10–7 (= (0.013)/(32)).”
Quote in the paperSubstantial claim - Interpretationown data
AC-to-AU editing by A1 requires a cofactor A1CF.
“Because the AC-to-AU mutations was not detected in A1 alone (Supplementary Fig. S5), it indicates that the AC-to-AU editing also requires a cofactor A1CF.”
Quote in the paperSubstantial claim - Interpretationnone given
Most APOBEC-mediated C-to-U mutations detected in our assay system may be either detrimental or neutral to the virus and will be lost in the viral infection cycle, thus missing in the databank consensus viral sequence.
“While most APOBEC-mediated C-to-U mutations detected in our assay system may be either detrimental or neutral to the virus and will be lost in the viral infection cycle, thus missing in the databank consensus viral sequence, some mutations beneficial to the virus's fitness will be selected for in the new viral strains.”
Quote in the paperSubstantial claim - Interpretationreasoning
It is possible to predict all possible target C sites in both coding and non-coding regions to be edited by these APOBECs.
“Unlike the random mutations caused by RNA replication or ROS, the presence of the finite number of the UC/AC motifs on the SARS-CoV-2 genomic RNA and the potentially correct prediction of the viral RNA structures suggest that it is possible to predict all the possible target C sites in both the coding and non-coding regions to be edited by these APOBECs.”
Quote in the paperSubstantial claim - Interpretationown data
Additional RNA structural features around UC/AC motifs play an important role in dictating whether a UC or AC site can be efficiently edited.
“Many of the UC and AC motifs in the SARS-CoV-2 RNA showed only the background level of C-to-U mutation (Supplementary Dataset File 2), which suggest that additional RNA structural features around the UC/AC motifs should play an important role in dictating whether a UC or AC site can be efficiently edited (Fig. 3).”
Quote in the paperSubstantial claim - Premisecitation
The pro-viral effect of A3A contrasts with the known anti-viral effect of APOBECs.
“These pro-viral effect of A3A contrast to the known anti-viral effect of APOBECs19–22.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [19] Olson, M. E., Harris, R. S. & Harki, D. A. APOBEC enzymes as targets for virus and cancer therapy. Cell Chem. Biol. 25, 36–49. https://doi.org/10.1016/j.chembiol.2017.10.007 (2018). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [20] Salter, J. D., Bennett, R. P. & Smith, H. C. The APOBEC protein family: United by structure, Divergent in Function. Trends Biochem. Sci. 41, 578–594. https://doi.org/10.1016/j.tibs.2016.05.001 (2016). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [21] Harris, R. S. & Dudley, J. P. APOBECs and virus restriction. Virology 479–480, 131–145. https://doi.org/10.1016/j.virol.2015.03.012 (2015). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [22] Chen, X. S. Insights into the structures and multimeric status of APOBEC proteins involved in viral restriction and other cellular functions. Viruses https://doi.org/10.3390/v13030497 (2021). source
Checked before — its earlier verdict is held back until a new check runs.
- Interpretationreasoning
Some mutations beneficial to the virus's fitness will be selected for in new viral strains.
“While most APOBEC-mediated C-to-U mutations detected in our assay system may be either detrimental or neutral to the virus and will be lost in the viral infection cycle, thus missing in the databank consensus viral sequence, some mutations beneficial to the virus's fitness will be selected for in the new viral strains.”
Quote in the paperSubstantial claim - Interpretationown data
C-to-U mutation at UC241 is selected for better viral fitness.
“The SARS-CoV-2 from patients detected all of these three mutations at different stages since early 2020, but only major circulating viral strains since early 2020 acquired the mutation at UC241 (Fig. 4C, Supplementary Fig. S6C), suggesting that C-to-U mutation at UC241 is selected for better viral fitness.”
Quote in the paperSubstantial claim - Premisecitation
Prior bioinformatic analyses suggested that some C-to-U mutations in SARS-CoV-2 sequences may be caused by APOBEC proteins rather than random mutations by viral RNA polymerase or ROS.
“Prior bioinformatic analysis of the SARS-CoV-2 sequences suggested that some of the C-to-U mutations may be caused by APOBEC proteins instead of the random mutations caused by viral RNA polymerase during replication or ROS11,12,14,27,51,52.”
Quote in the paperSubstantial claim0 of 6 sources checked- cites [11] Di Giorgio, S., Martignano, F., Torcia, M. G., Mattiuz, G. & Conticello, S. G. Evidence for host-dependent RNA editing in the transcriptome of SARS-CoV-2. Sci. Adv. 6, eabb5813. https://doi.org/10.1126/sciadv.abb5813 (2020). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [12] Simmonds, P. Rampant C–>U hypermutation in the genomes of SARS-CoV-2 and other coronaviruses: Causes and consequences for their short- and long-term evolutionary trajectories. mSphere. https://doi.org/10.1128/mSphere.00408-20 (2020). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [14] Matyasek, R. & Kovarik, A. Mutation patterns of human SARS-CoV-2 and Bat RaTG13 coronavirus genomes are strongly biased towards C>U transitions, indicating rapid evolution in their hosts. Genes (Basel). https://doi.org/10.3390/genes11070761 (2020). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [27] Klimczak, L. J., Randall, T. A., Saini, N., Li, J. L. & Gordenin, D. A. Similarity between mutation spectra in hypermutated genomes of rubella virus and in SARS-CoV-2 genomes accumulated during the COVID-19 pandemic. PLoS One 15, e0237689. https://doi.org/10.1371/journal.pone.0237689 (2020). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [51] Sadykov, M., Mourier, T., Guan, Q. & Pain, A. Short sequence motif dynamics in the SARS-CoV-2 genome suggest a role for cytosine deamination in CpG reduction. J. Mol. Cell Biol. https://doi.org/10.1093/jmcb/mjab011 (2021). source
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- cites [52] Wang, R., Hozumi, Y., Zheng, Y. H., Yin, C. & Wei, G. W. Host immune response driving SARS-CoV-2 evolution. Viruses https://doi.org/10.3390/v12101095 (2020). source
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- Interpretationcitation
RNA-binding A1-cofactors could recruit A1 to target SARS-CoV-2 RNA for editing in infected tissue.
“Interestingly, both A1 cofactors A1CF and RBM47 were shown to physically interact with SARS-CoV-2 RNA in an interactome study56, offering indirect evidence that these RNA-binding A1-cofactors could recruit A1 to target SARS-CoV-2 RNA for editing in the infected tissue.”
Quote in the paperSubstantial claim - Interpretationreasoning
Such expression profiles make it possible for A3A and A1 + A1CF to edit the viral RNA genome in the real world.
“Such expression profiles make it possible for A3A and A1 + A1CF to edit the viral RNA genome in the real world.”
Quote in the paperSubstantial claim - Interpretationown data
Many AC-to-AU mutations in the SARS-CoV-2 genome from patients can be driven by A1 + A1CF mediated RNA-editing in the small intestine and liver with SARS-CoV-2 infection.
“These results indicate that many of the AC-to-AU mutations in the SARS-CoV-2 genome from patients can be driven by A1 + A1CF mediated RNA-editing in the small intestine and liver with SARS-CoV-2 infection.”
Quote in the paperSubstantial claim- Rests on an assumption: A1 + A1CF is expressed in the small intestine and liver during SARS-CoV-2 infection, enabling AC-to-AU editing in patients.
- Interpretationreasoning
This could explain why this mutation becomes prevalent in the widely circulating SARS-CoV-2 strains after January 2020.
“which could explain why this mutation becomes prevalent in the widely circulating SARS-CoV-2 strains after January 2020 (Fig. 4A–C).”
Quote in the paperSubstantial claim - Interpretationown data
The A3A deaminase activity plays a major role for promoting the viral replication and viral progeny production.
“Taken together, our results suggest that the A3A deaminase activity plays a major role for promoting the viral replication and viral progeny production.”
Quote in the paperSubstantial claim - Interpretationown data
The mutations resulting from APOBEC-mediated editing likely contribute to SARS-CoV-2 viral replication and fitness.
“Here we described the first experimental evidence demonstrating APOBEC enzymes, A1 + A1CF and A3A can target specific SARS-CoV-2 viral sequences for RNA editing, and the resulting mutations likely contribute to the viral replication and fitness.”
Quote in the paperSubstantial claim- Rests on an assumption: The HEK293T cell-based editing assay reflects APOBEC-mediated editing in natural SARS-CoV-2 infection.
- Premisecitation
UC241 is within the viral packaging signal sequence that has a stem-loop secondary structure in close proximity to stem-loop structures involved in replication and leader TRS-L.
“In fact, the UC241 is within the viral packaging signal sequence that has a stem-loop secondary structure which is in close proximity to the stem-loop structures involved in replication and leader transcription regulatory sequence (TRS-L)39 (Supplementary Fig. S14).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [39] Miao, Z., Tidu, A., Eriani, G. & Martin, F. Secondary structure of the SARS-CoV-2 5’-UTR. RNA Biol. 18, 447–456. https://doi.org/10.1080/15476286.2020.1814556 (2021). source
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- Premisecitation
Caco-2 expresses the virus receptor ACE2.
“We used lentiviral transfection to construct stable Caco-2 cell lines expressing A3A, A3G, and A1 + A1CF to study the effect of APOBEC on SARS-CoV-2 replication because Caco-2 expresses the virus receptor ACE242.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [42] Chu, H. et al. Comparative tropism, replication kinetics, and cell damage profiling of SARS-CoV-2 and SARS-CoV with implications for clinical manifestations, transmissibility, and laboratory studies of COVID-19: An observational study. Lancet Microbe 1, e14–e23. https://doi.org/10.1016/S2666-5247(20)30004-5 (2020). source
Checked before — its earlier verdict is held back until a new check runs.
- Interpretationreasoning
The C241 to U mutation should not be related to a change of a viral protein function, such as cell surface receptor binding or polyprotein processing.
“Therefore, this C241 to U mutation should not be related to a change of a viral protein function, such as cell surface receptor binding or polyprotein processing.”
Quote in the paperSubstantial claim - Interpretationown data
The deaminase activity of A3A to mutate the viral genome plays a critical role in the pro-viral effect.
“The data indicate that the deaminase activity of A3A to mutate the viral genome plays a critical role in the pro-viral effect even though a minor deamination-independent enhancement effect could not be ruled out.”
Quote in the paperSubstantial claim- Rests on an assumption: The inactive-A3A mutant used lacks deaminase activity.
- Interpretationown data
SARS-CoV-2 can take advantage of APOBEC-mediated mutation for their fitness and evolution.
“These results suggest that SARS-CoV-2 can take advantage of APOBEC-mediated mutation for their fitness and evolution.”
Quote in the paperSubstantial claim - Interpretationcitation
RBM47 may also enable A1 to perform AC-to-AU editing of SARS-CoV-2 RNA.
“Given the closely overlapping RNA target and editing efficiency by another A1-cofactor RBM4728,32,35,50, it’s likely that RBM47 may also enable A1 to perform AC-to-AU editing of SARS-CoV-2 RNA.”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [28] Wolfe, A. D., Arnold, D. B. & Chen, X. S. Comparison of RNA editing activity of APOBEC1-A1CF and APOBEC1-RBM47 complexes reconstituted in HEK293T cells. J. Mol. Biol. 431, 1506–1517. https://doi.org/10.1016/j.jmb.2019.02.025 (2019). source
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- cites [32] Fossat, N. et al. C to U RNA editing mediated by APOBEC1 requires RNA-binding protein RBM47. EMBO Rep. 15, 903–910. https://doi.org/10.15252/embr.201438450 (2014). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [35] Wolfe, A. D., Li, S., Goedderz, C. & Chen, X. S. The structure of APOBEC1 and insights into its RNA and DNA substrate selectivity. NAR Cancer 2, zcaa027. https://doi.org/10.1093/narcan/zcaa027 (2020). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [50] Blanc, V. et al. Apobec1 complementation factor (A1CF) and RBM47 interact in tissue-specific regulation of C to U RNA editing in mouse intestine and liver. RNA 25, 70–81. https://doi.org/10.1261/rna.068395.118 (2019). source
Checked before — its earlier verdict is held back until a new check runs.
- Interpretationreasoning
The C241U mutation may be a beneficial mutation for viral replication and progeny production even in cell culture infection assay.
“This observation suggests that the C241U mutation may be a beneficial mutation for viral replication and progeny production even in cell culture infection assay.”
Quote in the paperSubstantial claim - Premisecitation
A1 cofactors A1CF and RBM47 physically interact with SARS-CoV-2 RNA.
“Interestingly, both A1 cofactors A1CF and RBM47 were shown to physically interact with SARS-CoV-2 RNA in an interactome study56, offering indirect evidence that these RNA-binding A1-cofactors could recruit A1 to target SARS-CoV-2 RNA for editing in the infected tissue.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [56] Schmidt, N. et al. The SARS-CoV-2 RNA-protein interactome in infected human cells. Nat. Microbiol. 6, 339–353. https://doi.org/10.1038/s41564-020-00846-z (2021). source
Checked before — its earlier verdict is held back until a new check runs.
- Probably not a substantial claim. 20
- It may state two separate claims as one. 35
- The quote only partly states this claim. 1
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe seven APOBEC3 subfamilies (including A3A to A3H) restrict DNA and RNA viruses.
“The seven APOBEC3 subfamilies (including A3A to A3H) are reported to restrict DNA and RNA viruses (reviewed in Refs.21,22).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [21] Harris, R. S. & Dudley, J. P. APOBECs and virus restriction. Virology 479–480, 131–145. https://doi.org/10.1016/j.virol.2015.03.012 (2015). source
The ‘Positive selection and copy number variation’ section (page unavailable) identifies seven human APOBEC3 genes. The HIV-restriction section reports restriction by A3D, A3F, A3G and A3H, while ‘DNA viruses and the APOBEC family’ describes restriction by other APOBEC3 members. The review therefore supports restriction of RNA retroviruses and DNA viruses by APOBEC3 proteins, but not the implication that all seven have been shown to restrict both types. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [22] Chen, X. S. Insights into the structures and multimeric status of APOBEC proteins involved in viral restriction and other cellular functions. Viruses https://doi.org/10.3390/v13030497 (2021). source
Probably not a substantial claim. It may state two separate claims as one.
PremisecitationThe APOBEC proteins are a family of cytosine deaminases that can deaminate cytosine to uracil (C-to-U) in single-stranded nucleic acids and function in innate and adaptive immune responses to viral pathogens.
“The APOBEC proteins are a family of cytosine deaminases that can deaminate cytosine to uracil (C-to-U) in single-stranded nucleic acids and function in a variety of biological processes, including innate and adaptive immune responses to viral pathogens (Refs.19–22 and references therein).”
Quote in the paperSubstantial claim1 of 4 sources checked- cites [19] Olson, M. E., Harris, R. S. & Harki, D. A. APOBEC enzymes as targets for virus and cancer therapy. Cell Chem. Biol. 25, 36–49. https://doi.org/10.1016/j.chembiol.2017.10.007 (2018). source
The Introduction identifies APOBEC-family enzymes as cytosine-to-uracil editors, and “HIV-Restrictive APOBECs” describes APOBEC3 enzymes deaminating viral single-stranded DNA as an innate defense. “Considerations for APOBEC Inhibitor Design” says the family member AID is essential for antibody diversification, supporting an adaptive-immune role, but the paper does not specifically connect that role to responses to viral pathogens. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [20] Salter, J. D., Bennett, R. P. & Smith, H. C. The APOBEC protein family: United by structure, Divergent in Function. Trends Biochem. Sci. 41, 578–594. https://doi.org/10.1016/j.tibs.2016.05.001 (2016). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [21] Harris, R. S. & Dudley, J. P. APOBECs and virus restriction. Virology 479–480, 131–145. https://doi.org/10.1016/j.virol.2015.03.012 (2015). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [22] Chen, X. S. Insights into the structures and multimeric status of APOBEC proteins involved in viral restriction and other cellular functions. Viruses https://doi.org/10.3390/v13030497 (2021). source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
PremisecitationRecent analysis of SARS-CoV-2 and rubella vaccine virus genome data derived from patients show predominant mutational patterns with specific signatures rather than random genetic variations, suggesting that host-factor induced mutations play an important role in shaping the viral genomic RNA mutational outcome and evolution.
“Recent analysis of SARS-CoV-2 and rubella vaccine virus genome data derived from patients show predominant mutational patterns with specific signatures rather than random genetic variations, suggesting that the host-factor induced mutations play an important role in shaping the viral genomic RNA mutational outcome and evolution11–14.”
Quote in the paperSubstantial claim4 of 4 sources checked- cites [11] Di Giorgio, S., Martignano, F., Torcia, M. G., Mattiuz, G. & Conticello, S. G. Evidence for host-dependent RNA editing in the transcriptome of SARS-CoV-2. Sci. Adv. 6, eabb5813. https://doi.org/10.1126/sciadv.abb5813 (2020). source
- cites [12] Simmonds, P. Rampant C–>U hypermutation in the genomes of SARS-CoV-2 and other coronaviruses: Causes and consequences for their short- and long-term evolutionary trajectories. mSphere. https://doi.org/10.1128/mSphere.00408-20 (2020). source
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured - cites [13] Perelygina, L. et al. Infectious vaccine-derived rubella viruses emerge, persist, and evolve in cutaneous granulomas of children with primary immunodeficiencies. PLoS Pathog. 15, e1008080. https://doi.org/10.1371/journal.ppat.1008080 (2019). source
- cites [14] Matyasek, R. & Kovarik, A. Mutation patterns of human SARS-CoV-2 and Bat RaTG13 coronavirus genomes are strongly biased towards C>U transitions, indicating rapid evolution in their hosts. Genes (Basel). https://doi.org/10.3390/genes11070761 (2020). source
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
Probably not a substantial claim. It may state two separate claims as one.
PremisecitationDatabase analysis of SARS-CoV-2 genomic variations showed an overwhelmingly high C-to-U mutation rate, accounting for about 40% of all single nucleotide variations, which was interpreted as a result of RNA editing by host APOBECs rather than random mutations.
“Interestingly, the database analysis of SARS-CoV-2 genomic variations showed an overwhelmingly high C-to-U mutation rate, account for about 40% of all single nucleotide variations, which was interpreted as a result of RNA editing by host APOBECs rather than random mutations11,12,14,27.”
Quote in the paperSubstantial claim4 of 4 sources checked- cites [11] Di Giorgio, S., Martignano, F., Torcia, M. G., Mattiuz, G. & Conticello, S. G. Evidence for host-dependent RNA editing in the transcriptome of SARS-CoV-2. Sci. Adv. 6, eabb5813. https://doi.org/10.1126/sciadv.abb5813 (2020). source
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured - cites [12] Simmonds, P. Rampant C–>U hypermutation in the genomes of SARS-CoV-2 and other coronaviruses: Causes and consequences for their short- and long-term evolutionary trajectories. mSphere. https://doi.org/10.1128/mSphere.00408-20 (2020). source
- cites [14] Matyasek, R. & Kovarik, A. Mutation patterns of human SARS-CoV-2 and Bat RaTG13 coronavirus genomes are strongly biased towards C>U transitions, indicating rapid evolution in their hosts. Genes (Basel). https://doi.org/10.3390/genes11070761 (2020). source
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured - cites [27] Klimczak, L. J., Randall, T. A., Saini, N., Li, J. L. & Gordenin, D. A. Similarity between mutation spectra in hypermutated genomes of rubella virus and in SARS-CoV-2 genomes accumulated during the COVID-19 pandemic. PLoS One 15, e0237689. https://doi.org/10.1371/journal.pone.0237689 (2020). source
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
It may state two separate claims as one.
PremisecitationA3A is expressed in lung epithelial cells, and the A3A expression level is significantly stimulated by SARS-CoV-2 infection in patients.
“A3A is expressed in lung epithelial cells, and, importantly, the A3A expression level is significantly stimulated by SARS-CoV-2 infection in patients47–49 (Supplementary Fig. S13A).”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [47] Heng, T. S., Painter, M. W. & Immunological Genome Project, C. The Immunological Genome Project: Networks of gene expression in immune cells. Nat. Immunol. 9, 1091–1094. https://doi.org/10.1038/ni1008-1091 (2008). source
- cites [48] Blanco-Melo, D. et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell 181, 1036–10451039. https://doi.org/10.1016/j.cell.2020.04.026 (2020). source
The Results section on COVID-19 patients reports induced interferon-stimulated genes in lung tissue, but does not identify A3A among them. Searches of our copy for A3A, APOBEC3A, and its expanded name found no passage establishing its expression in lung epithelial cells or significant induction in patients. (LLM, conf=0.73)
Experimental — accuracy not yet measured - cites [49] Xiong, Y. et al. Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients. Emerg. Microbes Infect. 9, 761–770. https://doi.org/10.1080/22221751.2020.1747363 (2020). source
The Results section reports gene-expression changes in patients’ bronchoalveolar lavage fluid and blood cells, but does not identify A3A as one of the changed genes or establish its expression in lung epithelial cells. Searches for A3A, APOBEC3A, and lung epithelial cells found no passage addressing the specific claim. (LLM, conf=0.72)
Experimental — accuracy not yet measured
Probably not a substantial claim.
PremisecitationAPOBEC proteins play an important role in immune responses against DNA and RNA viral pathogens.
“Since APOBEC proteins play an important role in immune responses against DNA and RNA viral pathogens (Refs.19–22 and references therein), we also investigated the possible effects of the three APOBECs on SARS-CoV-2 replication and progeny production in our experimental system (Fig. 5A).”
Quote in the paperSubstantial claim4 of 4 sources checked- cites [19] Olson, M. E., Harris, R. S. & Harki, D. A. APOBEC enzymes as targets for virus and cancer therapy. Cell Chem. Biol. 25, 36–49. https://doi.org/10.1016/j.chembiol.2017.10.007 (2018). source
- cites [20] Salter, J. D., Bennett, R. P. & Smith, H. C. The APOBEC protein family: United by structure, Divergent in Function. Trends Biochem. Sci. 41, 578–594. https://doi.org/10.1016/j.tibs.2016.05.001 (2016). source
- cites [21] Harris, R. S. & Dudley, J. P. APOBECs and virus restriction. Virology 479–480, 131–145. https://doi.org/10.1016/j.virol.2015.03.012 (2015). source
- cites [22] Chen, X. S. Insights into the structures and multimeric status of APOBEC proteins involved in viral restriction and other cellular functions. Viruses https://doi.org/10.3390/v13030497 (2021). source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
FindingcitationA3A showed a preferred dinucleotide UC motif for editing.
“A3A showed a preferred dinucleotide UC motif, consistent with previous reports about the preferred motif for A3A-mediated editing of cellular RNA targets25,54.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [25] Sharma, S. et al. APOBEC3A cytidine deaminase induces RNA editing in monocytes and macrophages. Nat. Commun. 6, 6881. https://doi.org/10.1038/ncomms7881 (2015). source
- cites [54] Buisson, R. et al. Passenger hotspot mutations in cancer driven by APOBEC3A and mesoscale genomic features. Science https://doi.org/10.1126/science.aaw2872 (2019). source
In “APOBEC3A prefers substrate sites in DNA stem-loops” (page unavailable), the paper links A3A activity to TpC dinucleotides in DNA. “Sequence contexts regulating APOBEC3A and mutation accumulation in tumors” further identifies preferred DNA sequence contexts. It does not establish a UC preference for editing cellular RNA targets; the supported finding concerns the analogous DNA motif. (LLM, conf=0.86)
Experimental — accuracy not yet measured
It may state two separate claims as one.
PremisecitationA1 and its two known cofactors, A1CF and RBM47, are not expressed in the lungs but are expressed in the small intestine or liver that can also be infected by SARS-CoV-2.
“A1 and its two known cofactors, A1CF and RBM47, are not expressed in the lungs but are expressed in the small intestine or liver50 that can also be infected by SARS-CoV-2 (Supplementary Fig. S13B).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [50] Blanc, V. et al. Apobec1 complementation factor (A1CF) and RBM47 interact in tissue-specific regulation of C to U RNA editing in mouse intestine and liver. RNA 25, 70–81. https://doi.org/10.1261/rna.068395.118 (2019). source
The Abstract and Discussion describe APOBEC1, A1CF, and RBM47 in adult mouse intestine and liver, supporting their presence in those tissues. Our copy does not establish that all three are absent from lungs (searched for lung expression). The SARS-CoV-2 statement is attached to a supplementary-figure citation, not this source. (LLM, conf=0.86)
Experimental — accuracy not yet measured
It may state two separate claims as one.
Findingown dataAmong all the C-to-U variations of the SARS-CoV-2 sequences in our analysis, AC-to-AU and UC-to-UU account for 38.23% and 31.83%, respectively, significantly higher than GC-to-GU and CC-to-CU that account for 15.44% and 14.50%, respectively.
“Interestingly, among all the C-to-U variations of the SARS-CoV-2 sequences in our analysis, AC-to-AU (preferred by A1) and UC-to-UU (preferred by A3A) account for 38.23% and 31.83%, respectively, significantly higher than GC-to-GU and CC-to-CU that account for 15.44% and 14.50%, respectively (Supplementary Fig. S4), indicating the significance of APOBEC editing on the viral mutation.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThese 3 sites all feature UC motifs and showed significant C-to-U editing by A3A in our assay results.
“as these 3 sites all feature UC motifs and showed significant C-to-U editing by A3A in our assay results (Fig. 4B, Supplementary Fig S6B, and Supplementary Dataset File 2).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataA3G did not show a clear motif preference here, possibly due to generally inefficient editing by A3G on a small number of edited sites (n = 11) in the limitedly selected SARS-CoV-2 regions in this study.
“However, A3G did not show a clear motif preference here, possibly due to generally inefficient editing by A3G on a small number of edited sites (n = 11) in the limitedly selected SARS-CoV-2 regions in this study (Fig. 2A).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataOut of 307 total C in the selected viral RNA segments, the number of significant target sites with A1 + A1CF is 135, A3A is 67, and A3G is 11.
“Out of 307 total C in the selected viral RNA segments, the number of significant target sites with A1 + A1CF is 135, A3A is 67, and A3G is 11 (Fig. 2A and Supplementary Dataset File 2).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataAnalysis of the top 30% editing efficiency (hotspot editing sites) distinctly shows that A3A strongly prefers the UC motif, whereas A1 + A1CF has a strong bias toward the AC motif.
“It distinctly shows that A3A strongly prefers the UC motif, whereas A1 + A1CF has a strong bias toward the AC motif.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataA3A prefers for an UCa/u trinucleotide motif and A1 + A1CF prefers ACu/a motif.
“Analysis of the sequence contexts around the significant target C sites (with ± 5 nucleotides from target C) showed that A3A prefers for an UCa/u trinucleotide motif and A1 + A1CF prefers ACu/a motif (Fig. 2A), which is consistent with the reported motif preference for RNA editing by A3A and A125,31.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [25] Sharma, S. et al. APOBEC3A cytidine deaminase induces RNA editing in monocytes and macrophages. Nat. Commun. 6, 6881. https://doi.org/10.1038/ncomms7881 (2015). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [31] Rosenberg, B. R., Hamilton, C. E., Mwangi, M. M., Dewell, S. & Papavasiliou, F. N. Transcriptome-wide sequencing reveals numerous APOBEC1 mRNA-editing targets in transcript 3’ UTRs. Nat. Struct. Mol. Biol. 18, 230–236. https://doi.org/10.1038/nsmb.1975 (2011). source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
Findingown dataC-to-U editing by all three APOBECs is detected, with A1 + A1CF and A3A showing much higher editing than A3G.
“The C-to-U editing by all three APOBECs is detected, with A1 + A1CF and A3A showing much higher editing than A3G (Fig S2).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThe top 3 AC sites with the highest editing efficiency by A1 + A1CF could form a relatively stable stem-loop structure, with relatively high U/G/A contents downstream of the target C.
“We analyzed the RNA features around the top 3 AC sites with the highest editing efficiency by A1 + A1CF (Fig. 3A). The result showed that they could form a relatively stable stem-loop structure, with relatively high U/G/A contents downstream of the target C (Fig. 3A).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataNo DNA C-to-U mutation was detected, but specific RNA C-to-U changes on the mRNA transcript were present in a frequency consistent with our SSS results obtained in the presence of A1 + A1CF or A3A.
“No DNA C-to-U mutation was detected, but specific RNA C-to-U changes on the mRNA transcript were present in a frequency consistent with our SSS results obtained in the presence of A1 + A1CF (e.g., C16049, C16054, and C16092, etc.) or A3A (C16063) (Supplementary Fig. S5).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataA3A-E72A also showed slight enhancement of viral RNA replication and viral progeny yield.
“Interestingly, A3A-E72A also showed slight enhancement of viral RNA replication (Supplementary Fig. S10A) and viral progeny yield (Supplementary Fig. S10B).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataThe relative editing efficiency of these motif sites varies greatly, such as between 0.0041 and 22.15% for A1 + A1CF, and between 0.0040 and 4.46% for A3A.
“the relative editing efficiency of these motif sites vary greatly, such as between 0.0041 and 22.15% for A1 + A1CF, and between 0.0040 and 4.46% for A3A (Supplementary Dataset File 2).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataA3A and A1 + A1CF, but not A3G, are expressed in the human organs and cell types infected by SARS-CoV-2.
“While the editing of SARS-CoV-2 RNA by A3A and A1 + A1CF has been demonstrated in our cell culture system, the analysis of the expression profiles reveals that A3A and A1 + A1CF, but not A3G, are expressed in the human organs and cell types infected by SARS-CoV-2 (Supplementary Fig. S13A,B).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataA1 + A1CF and A3A can target specific SARS-CoV-2 viral sequences for RNA editing.
“Here we described the first experimental evidence demonstrating APOBEC enzymes, A1 + A1CF and A3A can target specific SARS-CoV-2 viral sequences for RNA editing, and the resulting mutations likely contribute to the viral replication and fitness.”
Quote in the paperSubstantial claim- Rests on an assumption: The HEK293T cell-based editing assay reflects APOBEC-mediated editing in natural SARS-CoV-2 infection.
It may state two separate claims as one.
Findingown dataWhile APOBEC-mediated C to U mutations were detected in all five sites on the viral RNA from infected Caco-2 cells using Sanger sequencing, significant C to U mutation was detected only for C241U at 72 and 96 h post infection.
“In summary, while APOBEC-mediated C to U mutations were detected in all five sites on the viral RNA from infected Caco-2 cells using Sanger sequencing, significant C to U mutation was detected only for C241U at 72 and 96 h post infection.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThe UC241 to UU241 mutation, a site highly edited by A3A in our study, is within the viral packaging signal and near the viral replication regulation area at the 5′UTR.
“This is consistent, among other things, with the observation that the UC241 to UU241 mutation, a site highly edited by A3A in our study, is within the viral packaging signal and near the viral replication regulation area at the 5′UTR (Supplementary Fig. S14), which could explain why this mutation becomes prevalent in the widely circulating SARS-CoV-2 strains after January 2020 (Fig. 4A–C).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown dataA slight but statistically non-significant increase in editing at C16054 and C23535 96 h post viral infection was observed.
“The results showed a slight but statistically non-significant increase in editing at C16054 and C23535 96 h post viral infection (Supplementary Fig. S12A,B).”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationThe dominant new viral strain is the Omicron BA.5 which is the most antibody immune evasive against currently available vaccines.
“The dominant new viral strain is the Omicron BA.5 which is the most antibody immune evasive against currently available vaccines9.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [9] Wang, Q. et al. Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4, & BA.5. Nature https://doi.org/10.1038/s41586-022-05053-w (2022). source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
Interpretationown dataThe C-to-U mutation at UC241 occurred in early January 2020 and has rapidly become a signature of the dominant strains (including Delta and Omicron) that spread worldwide, strongly suggesting that this C-to-U mutation at UC241 may contribute to the better fitness for SARS-CoV-2.
“Surprisingly, the C-to-U mutation at UC241 occurred in early January 2020 and has rapidly become a signature of the dominant strains (including Delta and Omicron) that spread worldwide (Fig. 4C and Supplementary Fig S6C), strongly suggesting that this C-to-U mutation at UC241 may contribute to the better fitness for SARS-CoV-2.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
PremisecitationSequencing data of SARS-CoV-2 from patients revealed persistent accumulation of new mutations over the last two years of the Covid19 pandemic, leading to the emergence of new viral strains that can be more transmissible or virulent or evade vaccines.
“However, sequencing data of SARS-CoV-2 from patients revealed persistent accumulation of new mutations over the last two years of the Covid19 pandemic, leading to the emergence of new viral strains that can be more transmissible or virulent5,6 or evade vaccines7–9.”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [5] Korber, B. et al. Tracking changes in SARS-CoV-2 spike: Evidence that D614G increases infectivity of the COVID-19 virus. Cell 182, 812–827819. https://doi.org/10.1016/j.cell.2020.06.043 (2020). source
- cites [6] Tasakis, R. N. et al. SARS-CoV-2 variant evolution in the United States: High accumulation of viral mutations over time likely through serial Founder Events and mutational bursts. PLoS One 16, e0255169. https://doi.org/10.1371/journal.pone.0255169 (2021). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [7] Garcia-Beltran, W. F. et al. Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity. Cell 184, 2523. https://doi.org/10.1016/j.cell.2021.04.006 (2021). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [8] Harvey, W. T. et al. SARS-CoV-2 variants, spike mutations and immune escape. Nat. Rev. Microbiol. 19, 409–424. https://doi.org/10.1038/s41579-021-00573-0 (2021). source
- cites [9] Wang, Q. et al. Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4, & BA.5. Nature https://doi.org/10.1038/s41586-022-05053-w (2022). source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationSARS-CoV-2 and other coronaviruses have moderate genetic variability because they have a built-in proofreading mechanism in their RdRP to correct errors during viral genome replication and transcription.
“Unlike most RNA viruses that exhibit high mutation rates (Ref.3 and references therein), SARS-CoV-2 and other coronaviruses have moderate genetic variability because they have built-in proofreading mechanism in their RNA-dependent RNA-polymerase (RdRP) to correct the errors during viral genome replication and transcription4.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [4] Robson, F. et al. Coronavirus RNA proofreading: Molecular basis and therapeutic targeting. Mol. Cell 80, 1136–1138. https://doi.org/10.1016/j.molcel.2020.11.048 (2020). source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
Interpretationown dataA3A generated these mutations on the viral RNA genome, and the mutations can be maintained, likely because these three mutations generated by A3A editing are not detrimental to the virus.
“These results suggest that A3A generated these mutations on the viral RNA genome, and the mutations can be maintained, likely because these three mutations generated by A3A editing are not determinantal to the virus.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataThe observed AC-to-AU mutations are most likely generated by A1 plus cofactor A1CF (or other A1 cofactors, such as RBM47); the UC-to-UU mutations by A3A in the sequence variation detected on the SARS-CoV-2 RNA segments.
“These results suggest that the observed AC-to-AU mutations are most likely generated by A1 plus cofactor A1CF (or other A1 cofactors, such as RBM4732); the UC-to-UU mutations by A3A in the sequence variation detected on the SARS-CoV-2 RNA segments (Fig. 2C).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [32] Fossat, N. et al. C to U RNA editing mediated by APOBEC1 requires RNA-binding protein RBM47. EMBO Rep. 15, 903–910. https://doi.org/10.15252/embr.201438450 (2014). source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe RNA editing by A1 + A1CF was previously reported to require a so-called mooring sequence that has a general stem-loop structure around the target C and contains relatively high U/G/A content downstream of the target C.
“The RNA editing by A1 + A1CF was previously reported to require a so-called mooring sequence that has a general stem-loop structure around the target C and contains relatively high U/G/A content downstream of the target C33,34.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [33] Sowden, M., Hamm, J. K. & Smith, H. C. Overexpression of APOBEC-1 results in mooring sequence-dependent promiscuous RNA editing. J. Biol. Chem. 271, 3011–3017. https://doi.org/10.1074/jbc.271.6.3011 (1996). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [34] Maris, C., Masse, J., Chester, A., Navaratnam, N. & Allain, F. H. NMR structure of the apoB mRNA stem-loop and its interaction with the C to U editing APOBEC1 complementary factor. RNA 11, 173–186. https://doi.org/10.1261/rna.7190705 (2005). source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
InterpretationreasoningTwo of these three mutations, UC203 and UC222, were detected in some of the SARS-CoV-2 sequences in late 2020 but are not persistently present in the main circulating strains, suggesting these two mutations may be neutral for the viral fitness.
“Two of these three mutations, UC203 and UC222, were detected in some of the SARS-CoV-2 sequences in late 2020 but are not persistently present in the main circulating strains, suggesting these two mutations may be neutral for the viral fitness.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataAmong these top 3 editing sites, editing at C16054 is significantly higher than at C23170, suggesting that, in addition to the possible involvement of long range RNA interactions, the editing efficiency also depends on the detailed local stem-loop structure and the position of the target C.
“Among these top 3 editing sites, editing at C16054 is significantly higher than at C23170 (Fig. 3A), suggesting that, in addition to the possible involvement of long range RNA interactions, the editing efficiency also depends on the detailed local stem-loop structure and the position of the target C.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
InterpretationreasoningMany of these AC, UC, and CC motif sites on the viral RNA have no detectable editing by A1 + A1CF, A3A, and A3G, respectively, suggesting that other RNA features beyond the dinucleotide sequence motifs, such as the secondary and tertiary structures, must play a role in the editing efficiency of a particular motif site.
“Furthermore, many of these AC, UC, and CC motif sites on the viral RNA have no detectable editing by A1 + A1CF, A3A, and A3G, respectively, suggesting that other RNA features beyond the dinucleotide sequence motifs, such as the secondary and tertiary structures, must play a role in the editing efficiency of a particular motif site.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataThe C-to-U changes on the RNA are not caused by DNA mutation, but are the result of direct RNA editing mediated by A1 + A1CF and A3A in our cell-based assay system.
“These data indicate that the C-to-U changes on the RNA are not caused by DNA mutation, but are the result of direct RNA editing mediated by A1 + A1CF and A3A in our cell-based assay system.”
Quote in the paperSubstantial claimIt may state two separate claims as one. The quote only partly states this claim.
Study design and conductreasoningThe SSS system minimizes errors from PCR amplification and sequencing.
“To minimize the sequencing errors when evaluating the C-to-U RNA editing, we employed the SSS system, a targeted next generation deep-sequencing system, with slightly adapted protocols (Fig. 1D, see Methods in SI)29,30.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [29] Kinde, I., Wu, J., Papadopoulos, N., Kinzler, K. W. & Vogelstein, B. Detection and quantification of rare mutations with massively parallel sequencing. Proc. Natl. Acad. Sci. U. S. A. 108, 9530–9535. https://doi.org/10.1073/pnas.1105422108 (2011). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [30] Eboreime, J., Choi, S. K., Yoon, S. R., Arnheim, N. & Calabrese, P. Estimating exceptionally rare germline and somatic mutation frequencies via next generation sequencing. PLoS One 11, e0158340. https://doi.org/10.1371/journal.pone.0158340 (2016). source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
PremisecitationCaco-2 cell line expresses ACE2 receptor and thus is a model cell line for SARS-CoV-2 infection and replication studies.
“we used the human colon epithelial cell line Caco-2 that expresses ACE2 receptor and thus is a model cell line for SARS-CoV-2 infection and replication studies42.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [42] Chu, H. et al. Comparative tropism, replication kinetics, and cell damage profiling of SARS-CoV-2 and SARS-CoV with implications for clinical manifestations, transmissibility, and laboratory studies of COVID-19: An observational study. Lancet Microbe 1, e14–e23. https://doi.org/10.1016/S2666-5247(20)30004-5 (2020). source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenA randomized guide RNA was used to generate a Caco-2 cell line as a negative control.
“A randomized guide RNA was used to generate a Caco-2 cell line as a negative control.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
InterpretationreasoningThe UC241 to UU241 mutation may impact viral RNA packaging and virion production, and may even impact RNA replication, sub-genomic production, or/and translation efficiency of downstream proteins to endow the virus with better fitness.
“Thus, this UC241 to UU241 mutation may impact the viral RNA packaging and virion production, and may even impact RNA replication, sub-genomic production, or/and the translation efficiency of the downstream proteins to endow the virus with better fitness.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenWestern blot analysis was performed from three independent transfections.
“Western blot analysis were performed from three independent transfections using FLAG-tagged APOBECs and HA-tagged A1CF.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
PremisecitationThe 5′UTR region of SARS-CoV-2 has important function in regulating protein expression and viral RNA replication and virion packaging.
“However, the 5′UTR region of SARS-CoV-2 has important function in regulating protein expression and viral RNA replication and virion packaging39,40,57.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [39] Miao, Z., Tidu, A., Eriani, G. & Martin, F. Secondary structure of the SARS-CoV-2 5’-UTR. RNA Biol. 18, 447–456. https://doi.org/10.1080/15476286.2020.1814556 (2021). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [40] Nomburg, J., Meyerson, M. & DeCaprio, J. A. Pervasive generation of non-canonical subgenomic RNAs by SARS-CoV-2. Genome Med. 12, 108. https://doi.org/10.1186/s13073-020-00802-w (2020). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [57] Guan, B. J., Su, Y. P., Wu, H. Y. & Brian, D. A. Genetic evidence of a long-range RNA–RNA interaction between the genomic 5’ untranslated region and the nonstructural protein 1 coding region in murine and bovine coronaviruses. J. Virol. 86, 4631–4643. https://doi.org/10.1128/JVI.06265-11 (2012). source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim.
Study design and conductown dataExpression of the APOBEC proteins was verified by Western blot.
“Expression of these APOBEC proteins was verified by Western blot.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenThe qPCR of internal actin RNA abundance level is used as a control.
“The qPCR of the internal actin RNA abundance level is used as a control by using actin-specific primers.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataCritical factors dictating RNA-editing efficiency by A3A and A1 + A1CF include a dinucleotide motif UC for A3A or AC for A1 as well as certain RNA structural features around the target C.
“Critical factors dictating the RNA-editing efficiency by these two APOBECs include a dinucleotide motif UC for A3A or AC for A1 as well as certain RNA structural features around the target C.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationSome cellular RNA targets with stem-loop structures are favored by A3A and A1 editing.
“Prior reports show that some cellular RNA targets with stem-loop structures are favored by A3A and A1 editing25,28,34,54.”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [25] Sharma, S. et al. APOBEC3A cytidine deaminase induces RNA editing in monocytes and macrophages. Nat. Commun. 6, 6881. https://doi.org/10.1038/ncomms7881 (2015). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [28] Wolfe, A. D., Arnold, D. B. & Chen, X. S. Comparison of RNA editing activity of APOBEC1-A1CF and APOBEC1-RBM47 complexes reconstituted in HEK293T cells. J. Mol. Biol. 431, 1506–1517. https://doi.org/10.1016/j.jmb.2019.02.025 (2019). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [34] Maris, C., Masse, J., Chester, A., Navaratnam, N. & Allain, F. H. NMR structure of the apoB mRNA stem-loop and its interaction with the C to U editing APOBEC1 complementary factor. RNA 11, 173–186. https://doi.org/10.1261/rna.7190705 (2005). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [54] Buisson, R. et al. Passenger hotspot mutations in cancer driven by APOBEC3A and mesoscale genomic features. Science https://doi.org/10.1126/science.aaw2872 (2019). source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationA high mutation rate of C in AC motif was noted in SARS-CoV-2 and Rubella Virus by prior bioinformatic analysis.
“A high mutation rate of C in AC motif was also noted in SARS-CoV-2 and Rubella Virus by prior bioinformatic analysis3,11,27.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [3] Kockler, Z. W. & Gordenin, D. A. From RNA world to SARS-CoV-2: The edited story of RNA viral evolution. Cells https://doi.org/10.3390/cells10061557 (2021). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [11] Di Giorgio, S., Martignano, F., Torcia, M. G., Mattiuz, G. & Conticello, S. G. Evidence for host-dependent RNA editing in the transcriptome of SARS-CoV-2. Sci. Adv. 6, eabb5813. https://doi.org/10.1126/sciadv.abb5813 (2020). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [27] Klimczak, L. J., Randall, T. A., Saini, N., Li, J. L. & Gordenin, D. A. Similarity between mutation spectra in hypermutated genomes of rubella virus and in SARS-CoV-2 genomes accumulated during the COVID-19 pandemic. PLoS One 15, e0237689. https://doi.org/10.1371/journal.pone.0237689 (2020). source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
Study design and conductnone givenThe SSS approach avoids the high error rate associated with conventional NGS sequencing used for obtaining currently deposited SARS-CoV-2 viral sequences.
“The SSS approach also avoid the high-error rate associated with the conventional NGS sequencing used for obtaining the currently deposited SARS-CoV-2 viral sequences.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationMany human cell types expressing ACE2 in multiple organs can be infected by SARS-CoV-2, including (but not limited to) the lungs, heart, small intestine, and liver.
“Many human cell types expressing ACE2 in multiple organs can be infected by SARS-CoV-2, including (but not limited to) the lungs, heart, small intestine, and liver45,46.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [45] Zheng, Y. Y., Ma, Y. T., Zhang, J. Y. & Xie, X. COVID-19 and the cardiovascular system. Nat. Rev. Cardiol. 17, 259–260. https://doi.org/10.1038/s41569-020-0360-5 (2020). source
- cites [46] Trypsteen, W., Van Cleemput, J., Snippenberg, W. V., Gerlo, S. & Vandekerckhove, L. On the whereabouts of SARS-CoV-2 in the human body: A systematic review. PLoS Pathog. 16, e1009037. https://doi.org/10.1371/journal.ppat.1009037 (2020). source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
InterpretationreasoningSARS-CoV-2 can turn the tables on the APOBEC mutational defense system for its evolution, including improvement of viral RNA replication, protein expression, evasion of host immune responses, and receptor binding and cell entry.
“If so, SARS-CoV-2 can then turn the tables on the APOBEC mutational defense system for its evolution, including (but not limited to) the improvement of viral RNA replication, protein expression, evasion of host immune responses, and receptor binding and cell entry.”
Quote in the paperNot a substantial claimProbably not a substantial claim.
PremisecitationMutations outside protein-coding ORFs of SARS-CoV-2 were previously designated as non-functional changes.
“Mutations outside protein-coding ORFs of SARS-CoV-2 were previously designated as non-functional changes3.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] Kockler, Z. W. & Gordenin, D. A. From RNA world to SARS-CoV-2: The edited story of RNA viral evolution. Cells https://doi.org/10.3390/cells10061557 (2021). source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim.
PremisecitationA1 was not previously thought as a candidate that could edit the SARS-CoV-2 genome because of its target specificity and lack of expression in lungs, the primary target tissues of SARS-CoV-2 infection.
“A1 was not previously thought as a candidate which could edit the SARS-CoV-2 genome because of its target specificity and lack of expression in lungs, the primary target tissues of SARS-CoV-2 infection55.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [55] Ratcliff, J. & Simmonds, P. Potential APOBEC-mediated RNA editing of the genomes of SARS-CoV-2 and other coronaviruses and its impact on their longer term evolution. Virology 556, 62–72. https://doi.org/10.1016/j.virol.2020.12.018 (2021). source
Checked before — its earlier verdict is held back until a new check runs.
The paper relies on this without support.
There is no report on direct experimental evidence to demonstrate if APOBECs can edit the SARS-CoV-2 genome.
“However, there is no report on the direct experimental evidence to demonstrate if APOBECs can edit the SARS-CoV-2 genome and, if so, what is the extent of editing on the viral genome by different APOBECs, and the potential effect of the APOBEC-editing on the virus.”
The paper relies on this without support.
A1 + A1CF is expressed in the small intestine and liver during SARS-CoV-2 infection, enabling AC-to-AU editing in patients.
“These results indicate that many of the AC-to-AU mutations in the SARS-CoV-2 genome from patients can be driven by A1 + A1CF mediated RNA-editing in the small intestine and liver with SARS-CoV-2 infection.”
The paper relies on this without support.
The inactive-A3A mutant used lacks deaminase activity.
“even though some increase of replication and progeny production was also observed in the inactive-A3A mutant expressing cell line (Supplementary Fig. S10).”
The paper relies on this without support.
The HEK293T cell-based editing assay reflects APOBEC-mediated editing in natural SARS-CoV-2 infection.
“Here we described the first experimental evidence demonstrating APOBEC enzymes, A1 + A1CF and A3A can target specific SARS-CoV-2 viral sequences for RNA editing, and the resulting mutations likely contribute to the viral replication and fitness.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Conflicting locations of the reporter intron
MinorThe Results place the AAV intron in the middle of eGFP, whereas the Figure 1 caption places it between eGFP and the viral RNA segment.
“An AAV intron is inserted in the middle of eGFP”
“an RNA containing an AAV intron between the eGFP and the viral RNA segment”
Different UC-to-UU mutation percentages for the same cited analysis
MinorThe Results give 31.83% for UC-to-UU mutations, while the Discussion gives 31.2% for UC-motif mutations and cites the same Supplementary Fig. S4. The difference is too large to be rounding.
“UC-to-UU (preferred by A3A) account for 38.23% and 31.83%, respectively”
“higher AC motif mutations (38.3%) than UC motif mutations (31.2%) (Supplementary Fig. S4)”
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Self-citationIdentification of RBM46 as A Novel APOBEC1 Cofactor for C-to-U RNA-Editing Activity
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HSV-1 miRNAs are post-transcriptionally edited in latently infected human ganglia
Zubković, A., Gomes, C., Parchure, A., Cesarec, M., Ferenčić, A., Rokić, F., Jakovac, H., Whitford, A. L., Dochnal, S. A., Cliffe, A. R., et al. (2023) · Journal of Virology · doi:10.1128/jvi.00730-23 · Cited by 7
The Impact of First-Time SARS-CoV-2 Infection on Human Anelloviruses
Timmerman, A. L., Commandeur, L., Deijs, M., Burggraaff, M. G. J. M., Lavell, A. H. A., van der Straten, K., Tejjani, K., van Rijswijk, J., van Gils, M. J., Sikkens, J. J., et al. (2024) · Viruses · doi:10.3390/v16010099 · Cited by 7
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RNA editing sites and triplet usage in exomes of bat RNA virus genomes of the family Paramyxoviridae
Sharma, D., & Chakraborty, S. (2024) · Microbial Pathogenesis · doi:10.1016/j.micpath.2024.106796 · Cited by 7
Differential RNA editing landscapes in host cell versus the SARS-CoV-2 genome
Kurkowiak, M., Fletcher, S., Daniels, A., Mozolewski, P., Silvestris, D. A., Król, E., Marek-Trzonkowska, N. M., Hupp, T. R., & Tait‐Burkard, C. (2023) · iScience · doi:10.1016/j.isci.2023.108031 · Cited by 7
Two codes of RNA editing by deamination in human diseases
Min, D. J., Lee, S., Lee, Y.-S., & Cho, J. (2026) · Experimental & Molecular Medicine · doi:10.1038/s12276-025-01633-8 · Cited by 6
Dudley, J. P. (2023) · PLoS Pathogens · doi:10.1371/journal.ppat.1011364 · Cited by 6
Potential Role of APOBEC3 Family Proteins in SARS-CoV-2 Replication
Begum, M. M., Bokani, A., Rajib, S. A., Soleimanpour-Moghadam, M., Maeda, Y., Yoshimura, K., Satou, Y., Ebrahimi, D., & Ikeda, T. (2024) · Viruses · doi:10.3390/v16071141 · Cited by 6
Dumm, A. J., Zheng, A. Y., Butler, T. J., Kulikowicz, T., George, J. C., Bombard, P. T., Sommers, J. A., Ding, J., & Brosh, R. M. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf447 · Cited by 6
A single mutation may contribute to accelerated evolution of SARS-CoV-2 toward Omicron
Lin, X., Sha, Z., Zhang, C., Adler, J. M., Vidal, R. M., Langner, C., Fu, B., Xiong, Y., Tan, M., Jiang, C., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-62300-0 · Cited by 6
Self-citationElkin, M. E., & Xingquan Zhu, A. (2025) · Communications Biology · doi:10.1038/s42003-024-07262-7 · Cited by 6
Human DNA tumor viruses evade uracil-mediated antiviral immunity
Stewart, J. A., & Damania, B. (2023) · PLoS Pathogens · doi:10.1371/journal.ppat.1011252 · Cited by 6
Mitigation approaches of monkeypox outbreaks in developing countries
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Attenuation and Degeneration of SARS-CoV-2 Despite Adaptive Evolution
Liu, Y. (2023) · Cureus · doi:10.7759/cureus.33316 · Cited by 5
HAMMER: hairpin-based APOBEC3A-mediated mRNA editing reporter
Chen, Y., Mullally, C. D., Stefanovska, B., & Harris, R. S. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag302 · Cited by 4
APOBEC3-Related Editing and Non-Editing Determinants of HIV-1 and HTLV-1 Restriction
Leong, S., Nasser, H., & Ikeda, T. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26041561 · Cited by 4
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Adenosine modifications impede SARS-CoV-2 RNA-dependent RNA transcription
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Calculating and applying pathogen mutational spectra using MutTuiPreprint
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Sequence signatures within the genome of SARS-CoV-2 can be used to predict host source
Rudar, J., Kruczkiewicz, P., Vernygora, O. V., Golding, G. B., Hajibabaei, M., & Lung, O. (2024) · Microbiology Spectrum · doi:10.1128/spectrum.03584-23 · Cited by 3
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APOBEC3-related mutations in the spike protein-encoding region facilitate SARS-CoV-2 evolution
Shen, J., Xu, X., Fan, J., Chen, H., Zhao, Y., Huang, W., Liu, W., Zhang, Z., Cui, Q., Li, Q., et al. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e32139 · Cited by 3
Past, Present, and Future of RNA Modifications in Infectious Disease Research
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Proteomic applications in identifying protein-protein interactions
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In silico and experimental approaches for validating RNA editing events in transcriptomes
Wei, L. (2024) · RNA Biology · doi:10.1080/15476286.2024.2432729 · Cited by 2
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APOBEC cellular enzymes as ‘court jesters’ in SARS-CoV-2 evolution
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Mechanisms of APOBEC3 Packaging into HIV-1
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Engineered CBEs based on Macaca fascicularis A3A with improved properties for precise genome editing
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APOBEC3D excludes APOBEC3F from HIV-1 virions by competitive binding of RNA
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The Omicron variant of SARS-CoV-2
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How Did Latin America Face the SARS-CoV-2 Variants?
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Self-citationFluorescent shift assay for APOBEC-mediated RNA editing
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Testing for a wildlife reservoir of divergent SARS-CoV-2 in white-tailed deer
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APOBEC3B Promotes SARS-CoV-2 Through Activation of PKR/eIF2⍺ and AMPD2 Dysregulation
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Self-citationNucleoside Modifications in Novel Coronavirus SARS-CoV-2
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Metadata
- Authors
- Kim, K., Calabrese, P., Wang, S., Qin, C., Rao, Y., Feng, P., & Chen, X. S.
- Affiliations
- University of Southern California (US)
- Corresponding author
- Chen, Xiaojiang S.
- Venue
- Scientific Reports
- Published
- 2022-09-13
- Volume
- 12
- Issue
- 1
- Pages
- 14972-14972
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC9470679
- OpenAlex
- W4295346375
- Cited by
- 115
- References
- 71
- Citations by year
- 2026: 13 · 2025: 24 · 2024: 41 · 2023: 27 · 2022: 10
- FWCI
- 7.65
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- PubMed Central (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (AI150524)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- SARS-CoV-2, APOBEC3A, APOBEC1, APOBEC3G, viral RNA replication, viral fitness, viral evolution, host-virus interaction, Caco-2 cells, viral genome structure
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