Abstract
Mutations in the cytosine-5 RNA methyltransferase NSun2 cause microcephaly and other neurological abnormalities in mice and human. How post-transcriptional methylation contributes to the human disease is currently unknown. By comparing gene expression data with global cytosine-5 RNA methylomes in patient fibroblasts and NSun2-deficient mice, we find that loss of cytosine-5 RNA methylation increases the angiogenin-mediated endonucleolytic cleavage of transfer RNAs (tRNA) leading to an accumulation of 5′ tRNA-derived small RNA fragments. Accumulation of 5′ tRNA fragments in the absence of NSun2 reduces protein translation rates and activates stress pathways leading to reduced cell size and increased apoptosis of cortical, hippocampal and striatal neurons. Mechanistically, we demonstrate that angiogenin binds with higher affinity to tRNAs lacking site-specific NSun2-mediated methylation and that the presence of 5′ tRNA fragments is sufficient and required to trigger cellular stress responses. Furthermore, the enhanced sensitivity of NSun2-deficient brains to oxidative stress can be rescued through inhibition of angiogenin during embryogenesis. In conclusion, failure in NSun2-mediated tRNA methylation contributes to human diseases via stress-induced RNA cleavage.
Highlights
Mutations in the cytosine-5 RNA methyltransferase NSun2 cause microcephaly and other neurological abnormalities in mice and human
We show that post-transcriptional methylation of transfer RNAs (tRNA) is a major upstream regulator determining the intracellular concentration and identity of 50 tRNA-derived small RNA fragments. tRNA hypo-methylation caused by inhibition or lack of NSun2 allows angiogenin-mediated tRNA cleavage and leads to the accumulation of 50 tRNA fragments
These 50 tRNA fragments activate stressresponse pathways leading to reduced protein translation rates, decreased cell size and increased cell death in vitro and in vivo causing a syndromic disorder characterised by growth and neurodevelopmental deficiencies in mice and human
Summary
Mutations in the cytosine-5 RNA methyltransferase NSun cause microcephaly and other neurological abnormalities in mice and human. It is known that NSun is a conserved RNA methyltransferase that modifies cytosine-5 in transfer RNAs (tRNAs) and other non-coding RNA species (Brzezicha et al, 2006; Frye & Watt, 2006; Blanco et al, 2011; Hussain et al, 2013b; Khoddami & Cairns, 2013), but whether and how loss of RNA methylation can cause symptoms of these complex diseases is currently unknown. We reveal that fragmentation of tRNAs into short noncoding RNAs is perturbed in mouse and patient cells lacking the NSun protein, and identify aberrant accumulation of cleaved tRNAs as one mechanism by which mutations in a RNA methyltransferase can result in neurological abnormalities in mice and humans
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