The Tudor SND1 protein is an m6A RNA reader essential for replication of Kaposi’s sarcoma-associated herpesvirus

Abstract

<i>N</i>⁶-methyladenosine (m⁶A) is the most abundant internal RNA modification of cellular mRNAs. m⁶A is recognised by YTH domain-containing proteins, which selectively bind to m⁶A-decorated RNAs regulating their turnover and translation. Using an m⁶A-modified hairpin present in the Kaposi's sarcoma associated herpesvirus (KSHV) <i>ORF50</i> RNA, we identified seven members from the 'Royal family' as putative m⁶A readers, including SND1. RIP-seq and eCLIP analysis characterised the SND1 binding profile transcriptome-wide, revealing SND1 as an m⁶A reader. We further demonstrate that the m⁶A modification of the <i>ORF50</i> RNA is critical for SND1 binding, which in turn stabilises the <i>ORF50</i> transcript. Importantly, SND1 depletion leads to inhibition of KSHV early gene expression showing that SND1 is essential for KSHV lytic replication. This work demonstrates that members of the 'Royal family' have m⁶A-reading ability, greatly increasing their epigenetic functions beyond protein methylation.