Nonsense-mediated decay pathway in the Endoplasmic reticulum (ER-NMD)

This is one of five projects being offered in 2017 for one or two three year PhD students available in the Edinburgh Super-Resolution Interdisciplinary Consortium. ESRIC is a centre of excellence for super-resolution microscopy. Utilising expertise in molecular and cellular biology from the MRC Human Genetics Unit (HGU) at the University of Edinburgh and Biophysics from the Institute of Biological Chemistry, Biophysics and Bioengineering within Heriot-Watt University our collaboration enables cutting edge research at the interface of biology and biophotonics. ESRIC houses state-of-the-art imaging technologies alongside molecular and cell biology facilities whilst the ESRIC PhD programme offers the opportunity to gain interdisciplinary experience to address important research questions relevant for normal biology and human disease. As part of the PhD students will attend the Royal Microscopical Society accredited ESRIC summer-school and they will participate in our HGU PhD training programme.

Project description:
The Nonsense-mediated mRNA decay (NMD) pathway is a highly conserved surveillance mechanism that selectively degrades mRNAs harbouring premature termination codons (PTCs), preventing the synthesis of truncated proteins. In addition, this pathway also regulates the abundance of a large number of endogenous cellular RNAs and fine-tunes many physiological processes1.

We previously identified the NBAS gene (Neuroblastoma-amplified sequence) as a novel NMD factor in nematodes, zebrafish and mammals2. NBAS was also identified as a component of the Syntaxin 18 complex that is localised at the Endoplasmic reticulum (ER) and is required for vesicular trafficking and ER homeostasis3. We hypothesise that NBAS could be a component of a spatially distinct branch of NMD, an ER-NMD dedicated pathway that targets mRNAs harbouring a signal peptide sequence that are resistant to the canonical NMD pathway in the cytoplasm, whilst their translation is stalled.

We observed that the core NMD factor UPF1 localises to the cytoplasm, but also to the ER. In collaboration with Rory Duncan (Heriot Watt), we will analyse NBAS interactions with UPF1 and other NMD components using FRET-FLIM approaches. We will also test whether the localisation of NBAS to the ER is required for its role in NMD. Finally, in order to probe for the existence of an ER-NMD pathway that is dependent on NBAS, we will use single molecule RNA FISH (smFISH) coupled with high resolution microscopy to spatially map the location of NMD-induced mRNA degradation4. We will distinguish the localisation of NMD substrates by complementing smFISH with immunolocalisation of ER-specific markers. These experiments will reveal the subcellular localisation of ER-targeted NMD substrates and their dependence on NBAS.


How to Apply:
These positions would suit a motivated student who must have obtained a first or upper second class UK BSc honors degree, or equivalent for degrees obtained outside the UK, in molecular biology or a related discipline by September 2017.
Applicants should submit a CV, which includes the contact details of 2 references (including email addresses) and a covering letter (no more than 1000 words), indicating a specific project of interest and why the applicant wishes to join the PhD programme and project to [Email Address Removed] by 26 February.
Applicants must also submit an online application to our PhD programme via the University of Edinburgh degree finder (EUCLID system) following the instructions at:
We will not consider applications that have not been submitted to both [Email Address Removed] and EUCLID by the closing date.
If you have not heard from us by 13 March please consider your application unsuccessful (we will not be able to provide feedback on unsuccessful applications).

Eligibility:
This funded studentship is open only to UK students, or EU students if they have been studying in the UK for the previous 3 years or working in a related discipline in the UK. EU students coming from a discipline related to super-resolution imaging are also eligible to apply.