About the Project
How do cells keep making the right proteins when conditions become stressful? Protein synthesis is one of the most fundamental processes in biology, yet ribosomes do not move smoothly along every mRNA. They can slow down, pause or stall, particularly when cells are under stress. If these stalled ribosomes are not rescued, they can collide with following ribosomes, creating molecular traffic jams that disrupt gene expression and may contribute to disease (Refs 1 and 2).
This project will investigate how La-related proteins (LARPs), a family of RNA-binding proteins linked to cancer and other disorders, help cells respond to stalled and collided ribosomes. We recently discovered that one LARP, Slf1, associates with collided ribosomes and supports the continued translation of important oxidative-stress response mRNAs (Ref 3). This suggests that LARPs may act as specialised factors that help ribosomes recover and allow cells to adapt to stress. The next challenge is to understand how this works at the molecular level.
The student will use molecular biology, biochemistry and structural biology approaches to study how specific LARP proteins bind to collided ribosomes and influence translation. The project will provide hands-on training in techniques such as cloning, protein/RNA biochemistry, ribosome complex preparation and cryo-electron microscopy, with opportunities to connect molecular mechanisms to broader questions in gene regulation and cellular stress responses.
This project would suit a student with a strong interest in molecular biology, RNA biology, translation, biochemistry or structural biology, and who is keen to develop interdisciplinary skills at the interface of mechanistic cell biology and molecular structure. By the end of the project, the student will have contributed new insight into how cells control protein synthesis during stress and will have gained valuable training in quantitative, biochemical and structural approaches relevant to modern molecular bioscience.
Eligibility
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject. Candidates with laboratory experience in structural biology or with an interest in molecular biology and biochemistry are encouraged to apply, especially if they have obtained a MSc level qualification with relevant laboratory experience in molecular biology, structural biology or biochemistry of protein purification.
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 – on the application form select PhD Biochemistry Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester
If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk
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: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester
Funding Notes
Applications are invited from self-funded students. This project has a Band 3 (high) fee. Details of our different fee bands can be found on our website View Website
References
- CAP Joazeiro (2019) Mechanisms and functions of ribosome-associated protein quality control. Nature Rev Mol. Cell Biol. 20:368-83. REVIEW https://doi.org/10.1038/s41580-019-0118-2
- AA Pochopien, et al., (2021). Structure of Gcn1 bound to stalled and colliding 80S ribosomes. Proc Natl Acad Sci U S A. 118:e2022756118. doi: 10.1073/pnas.2022756118.
- MD Jennings, P Srivastava, CJ Kershaw, D Talavera, CM Grant, GD Pavitt (2023). Interaction of the La-related protein Slf1 with colliding ribosomes maintains translation of oxidative-stress responsive mRNAs. Nucleic Acids Res. 51:5755-5773.
- T Adomavicius, M Guaita, Yu Zhou, MD Jennings, Zakia Latif, AM Roseman, GD Pavitt (2019). The structural basis of translational control by eIF2 phosphorylation. Nat Commun. 10:2136. doi: 10.1038/s41467-019-10167-3.