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Intronic gene silencing: new mechanism of gene expression regulation and its relevance to cancer

  • Full or part time
    Dr M Gullerova
  • Application Deadline
    Friday, January 10, 2020
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

Project Description

Mammalian cells employ small RNAs (sRNAs) molecules to regulate gene expression in a pathway known as RNA interference (RNAi). Transfer RNAs (tRNAs) are essential for translation but also serve as a source for tRNA-derived small RNAs (tsRNAs).
We discovered that the endoribonuclease Dicer, a critical player in canonical RNAi, associates with actively transcribed tRNA genes, binds to alternatively folded tRNAs and processes them into tsRNAs. Dicer-dependent tsRNAs target the introns of many protein coding genes and long non-coding RNAs, leading to degradation of their nascent RNA. Importantly, tsRNAs target genes are significantly associated with disease phenotypes underpinning the biological importance of this pathway. We propose a mechanism for intronic gene silencing that is distinct from well-known post-transcriptional or transcriptional gene expression regulation.
Finally, we employ synthetic tsRNA targeting oncogenes to suppress aggressive cancer phenotype, which has promising applications in future cancer therapies (patent filed by Cancer Research UK).
We wish to understand why and how is intronic gene silencing de-regulated in cancer cells. Various latest state of art technologies in molecular biology and bioinformatics help us to investigate molecular basis of this novel regulatory pathway.

Funding Notes

4 Year DPhil Prize Studentships cover University fees, a tax free stipend of ~£17,009 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

Ciccia A, Elledge SJ. 2010. The DNA damage response: making it safe to play with knives. Molecular cell 40: 179-204.
Francia S, Michelini F, Saxena A, Tang D, de Hoon M, Anelli V, Mione M, Carninci P, d'Adda di Fagagna F. 2012. Site-specific DICER and DROSHA RNA products control the DNA-damage response. Nature 488: 231-235.
Harlen KM, Churchman LS. 2017. The code and beyond: transcription regulation by the RNA polymerase II carboxy-terminal domain. Nature reviews Molecular cell biology.
Hawley BR, Lu WT, Wilczynska A, Bushell M. 2017. The emerging role of RNAs in DNA damage repair. Cell death and differentiation.
Lee HC, Chang SS, Choudhary S, Aalto AP, Maiti M, Bamford DH, Liu Y. 2009. qiRNA is a new type of small interfering RNA induced by DNA damage. Nature 459: 274-277.
Michalik KM, Bottcher R, Forstemann K. 2012. A small RNA response at DNA ends in Drosophila. Nucleic acids research 40: 9596-9603.
Polo SE, Jackson SP. 2011. Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. Genes & development 25: 409-433.
Wei W, Ba Z, Gao M, Wu Y, Ma Y, Amiard S, White CI, Rendtlew Danielsen JM, Yang YG, Qi Y. 2012. A role for small RNAs in DNA double-strand break repair. Cell 149: 101-112.
Zaborowska J, Egloff S, Murphy S. 2016. The pol II CTD: new twists in the tail. Nature structural & molecular biology 23: 771-777.

How good is research at University of Oxford in Biological Sciences?

FTE Category A staff submitted: 223.80

Research output data provided by the Research Excellence Framework (REF)

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