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

Abstract

N⁶-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) ORF50 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 ORF50 RNA is critical for SND1 binding, which in turn stabilises the ORF50 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.

Keywords: RNA modification; infectious disease; m6A; microbiology; virus; virus infection.