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The role of RNA-methyltransferase NSUN2 in tsRNA biogenesis and DNA repair


Sir William Dunn School of Pathology

Dr M Gullerova Friday, January 08, 2021 Competition Funded PhD Project (Students Worldwide)

About the Project

Cytosine methylation is a widespread epigenetic modification employed for regulation of DNA expression through the interplay of special proteins that act as writers, readers and erasers of this chemical modification. Mammalian cells also utilise RNA cytosine methylation as signalling and regulatory strategy. NSUN2 is an RNA-specific cytosine5-methyltransferase that has been observed targeting messenger RNA [1] and small RNAs [2, 3], including transfer RNAs (tRNAs) [4]. Methylation of tRNA is known to affect the stability and folding of tRNA molecules [4]. tRNAs are very versatile molecules; in addition to their main translational function, they also provide source for tRNA-derived small RNAs (tsRNAs) [5]. tsRNAs have been discovered to participate into RNA interference (RNAi) pathway, a mechanism used for regulating the expression of hundreds of genes, including many disease and cancer-related genes. We and others have shown that the endoribonuclease Dicer, a main player in canonical RNAi pathway, binds to alternatively folded tRNAs [5]. We have also shown that in vitro-transcribed tRNAs can fold into an alternative structues and that, in the absence of Dicer, leads to accumulation such tRNA strucutres in vivo. Additionally, we have identified NSUN2 interaction with Dicer through mass spectrometry. Through state-of-the-art techniques such as Selective 2′ Hydroxyl Acylation analyzed by Primer Extension (SHAPE) and mass spectrometry, we aim at investigating tRNA folding and the sites of NSUN2 methylation. We also wish to further investigate the role of NSUN2 in Dicer-driven biogenesis of tsRNA and the interaction between NSUN2 and Dicer. Moreover, we wish to identify some NSUN2 partners, including erasers and readers. Furthermore, we aim to characterise functional features of NSUN2, including the RNA binding motif, which is at present time unknown.
Preliminary data from our group also showed that NSUN2 nuclear expression is increased upon DNA damage and that NSUN2 is recruited to the chromatin at sites of double-stranded DNA break. Dicer products are recently been linked to DNA repair [6]. Therefore, NSUN2 role in this context is promising but yet to be elucidated. We aim to investigate the role of NSUN2 in DNA damage and cell regulation in normal and cancer phenotypes.


Funding Notes

4 Year DPhil Prize Studentships cover full University fees, a tax free enhanced stipend of ~£17,285 pa, and up to £5,300 pa for research costs and travel. The competition is open to applicants from all countries. See View Website for full details and to apply.

References

[1] Zhang, X., Liu, Z., Yi, J., Tang, H., Xing, J., Yu, M., Tong, T., Shang, Y., Gorospe, M. and Wang, W., 2012. The tRNA methyltransferase NSun2 stabilizes p16 INK4 mRNA by methylating the 3′-untranslated region of p16. Nature communications, 3(1), pp.1-12.

[2] Yuan, S., Tang, H., Xing, J., Fan, X., Cai, X., Li, Q., Han, P., Luo, Y., Zhang, Z., Jiang, B. and Dou, Y., 2014. Methylation by NSun2 represses the levels and function of microRNA 125b. Molecular and cellular biology, 34(19), pp.3630-3641.

[3] Sajini, A.A., Choudhury, N.R., Wagner, R.E., Bornelöv, S., Selmi, T., Spanos, C., Dietmann, S., Rappsilber, J., Michlewski, G. and Frye, M., 2019. Loss of 5-methylcytosine alters the biogenesis of vault-derived small RNAs to coordinate epidermal differentiation. Nature communications, 10(1), pp.1-13.
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