Abstract
COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which infected >200 million people resulting in >4 million deaths. However, temporal landscape of the SARS-CoV-2 translatome and its impact on the human genome remain unexplored. Here, we report a high-resolution atlas of the translatome and transcriptome of SARS-CoV-2 for various time points after infecting human cells. Intriguingly, substantial amount of SARS-CoV-2 translation initiates at a novel translation initiation site (TIS) located in the leader sequence, termed TIS-L. Since TIS-L is included in all the genomic and subgenomic RNAs, the SARS-CoV-2 translatome may be regulated by a sophisticated interplay between TIS-L and downstream TISs. TIS-L functions as a strong translation enhancer for ORF S, and as translation suppressors for most of the other ORFs. Our global temporal atlas provides compelling insight into unique regulation of the SARS-CoV-2 translatome and helps comprehensively evaluate its impact on the human genome.
Highlights
COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which infected >200 million people resulting in >4 million deaths
A large fraction (11–22%) of SARS-CoV-2 Ribosome-protected mRNA fragment sequencing (RPF-seq) and QTI-seq reads were mapped to a translation initiation site (TIS)-L that is a noncanonical CUG codon (Fig. 3b and Supplementary Fig. 3b) and a vast majority (>95%) of the TIS-L reads were mapped to subgenomic RNA (sgRNA) (Fig. 3d and Supplementary Fig. 4a–c)
These results were consistently observed at various time points and for relaxed RNase I conditions (Fig. 3d, e), suggesting that translation regulation by TIS-L may be widespread in the SARS-CoV-2 translatome
Summary
COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which infected >200 million people resulting in >4 million deaths. Recent studies have reported that the overall genome structure of SARS-CoV-2 is similar to rest of the coronaviruses, containing ORFs 1a and 1b and other genes for structural proteins, spike (S), envelope (E), membrane (M), nucleocapsid (N), and accessory proteins, 3a, 6, 7a, 7b, 8, and 102,11. Whereas the viral genomic replication and transcription are driven by viral proteins, the translation process relies on the host machinery Observation of both viral and human translatome dynamics upon infection is crucial to understanding the molecular mechanism of the SARS-CoV-2 pathogenicity in humans. The SARS-CoV-2 transcriptome[11] and translatome[13] have been recently reported, no study has concomitantly provided the temporal landscape of both the viral and human transcriptome and translatome upon infection so far
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