Seminar

Cytosine-5 RNA Methylation in stem cells, stress and cancer

Sandra Blanco, PhD

Cytosine‐5 methylation (m5C) is one of the best characterised epigenetic modification found in DNA, however the cellular and molecular functions of the same modified nucleobase in RNA remain unclear. I have recently showed the physiological role of m5C in RNA and how alterations of this post-transcriptional modification contribute to human diseases. Mutations in the cytosine-5 RNA methyltransferase NSUN2 cause microcephaly and other neurodevelopment abnormalities in mice and human. Deletion of Nsun2 in mouse also causes tissue stem cell differentiation deficiencies. And in cancer, inhibition of NSUN2 increases tumour-initiating cells self-renewal potential and leads to cancer progression in mice. By analyzing global cytosine-5 RNA methylomes I have found that NSUN2 is a RNA methyltransferase of transfer RNA (tRNA). By comparing tRNA expression data in patient fibroblasts and Nsun2-deficient mice, I found that loss of cytosine-5 methylation increases the endonucleolytic cleavage of tRNAs leading to an accumulation of 5´ tRNA-derived small RNA fragments. The functional role of these tRNA-derived small RNAs is to prompt a stress-induced translational programme at the expenses of tissue differentiation. Thus, inhibition or loss of post-transcriptional cytosine-5 methylation locks stem cells and tumour-initiation cells in a distinct undifferentiated state by regulating the translational machinery. Paradoxically, this stress-induced translation inhibition renders tissue stem cells and tumour-initiation cells hypersensitive to cytotoxic stress, as tumour regeneration after treatment with cytotoxic agents is blocked.