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Translation of mRNA into proteins is a critical cellular biological process for all life. This requires ribosomes to act with an array of translation factors to decode mRNA sequences with precision so that decoding errors are avoided. It has become clear that ribosomes move along mRNAs with variable speeds and can encounter issues causing pauses in their movement. If ribosome stalls are unresolved, the next ribosome can collide forming structures called disomes. 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 (refs 1 and 2). Stalls and collisions of ribosomes are particularly problematic during cellular stress, such as oxidative stress caused by reactive oxygen species (ROS) that damage nucleic acids and proteins. All aerobic organisms are exposed to ROS stress during normal aerobic metabolism or following exposure to oxygen radicalgenerating compounds. Therefore it is important to understand cellular recovery mechanisms. We recently described a role for a La-related protein (LARP) called Slf1 acting at stalled and collided ribosomes, and our data suggest the LARP can prevent ribosomes shifting out of the normal reading frame and so help to kickstart the ribosome on its journey to complete the synthesis of proteins-- including key antioxidant enzymes (Ref 3).
The major goal of this project is therefore to understand better how LARP proteins interact with collided disomes and identify what other proteins are also working there. This will require biochemical purification of LARP-containing ribosomes and disomes and analysis of their composition by mass spectrometry, together with protein-protein cross-linking (ref – see later), and performing structural analysis by electron cryo-microscopy which enables 3D-models of protein complexes to be resolved (eg ref 4). This project aims to provide a mechanistic understanding of how LARP proteins control protein synthesis, which is important since human LARPs are implicated in disease processes including cancers.
Candidates with a background in biochemistry and structural biology are particularly encouraged to apply.
Eligibility
Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.
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
To be considered for this project you MUST submit a formal online application form - full details on eligibility how to apply can be found on the BBSRC DTP website https://www.bmh.manchester.ac.uk/study/research/funded-programmes/bbsrc-dtp/
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 Address Removed]
Equality, Diversity and Inclusion
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/
Funding Notes
References
2. AA Pochopien, et al., (2021). doi: 10.1073/pnas.2022756118.
3. MD Jennings, et al., (2023). Interaction of the La-related protein Slf1 with colliding ribosomes
maintains translation of oxidative-stress responsive mRNAs. Nucleic Acids Res. 51:5755-5773.
4. T Adomavicius, et al (2019). The structural basis of translational control by eIF2 phosphorylation.
Nat Commun. 10:2136. doi: 10.1038/s41467-019-10167-3.
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