Investigating the interaction of La related proteins with colliding ribosomes

The accurate translation of mRNA into the right proteins at the right time and place is a critical cellular biological process for all life. This requires ribosomes to interact with many translation factors and accessory proteins to decode mRNA sequences into the correct protein sequences. Any errors risk creating aberrant proteins which may cause stress and when not resolved lead to disease. It has become clear that ribosomes move along mRNAs with variable speeds and frequently encounter issues causing pauses or stalls in their journey so they can resolve encountered issues. If ribosome stalls are unresolved, they create ‘road blocks’ leading to ribosome collisions. It is now becoming clear that there are multiple reasons for ribosome stalls and several distinct mechanisms for resolving them, none of which are well understood, but which involve a range of ribosome associating factors (see eg refs 1 and 2).

La related proteins (LARPs) play critical regulatory roles interacting with mRNAs and ribosomes and are implicated in cancer progression and other disorders. We recently described a novel role for a La related protein (LARP) called Slf1 acting at stalled and collided ribosomes. Our data suggest the LARP can help resolve stalls and kickstart the ribosome on its journey to complete the synthesis of a subset of key stress-response proteins (Ref 3). We now wish to understand how this occurs. The consequence for cells is that with the LARP functioning they are able to cope with oxidative stress by reprogramming gene expression promoting the synthesis of antioxidant proteins. In contrast, cells are stress-hypersensitive when the LARP is inactivated.

The overall aim of this project is to improve mechanistic understanding of the role of specific LARP proteins binding to collided ribosomes. The project will involve a range of molecular techniques including molecular biology, biochemistry and structural biology including cryo EM and would be suitable for a candidate with prior experience of some of these techniques.

Outcome:

• The student will contribute to providing novel insight into fundamental molecular biology of protein synthesis control.
• The student will learn fundamental interdisciplinary and quantitative skills in structural molecular biology. 

Entry requirements

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related subject area. Master degree or lab experience is preferable, but not necessary.

Before you Apply

Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.

How To Apply

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor.

On the online application form select PhD Molecular Biology.

For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit https://www.bmh.manchester.ac.uk/study/research/programmes/integrated-teaching/

Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered.

If you have any queries regarding making an application please contact our admissions team [email protected].

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