Details
Phase-separated biomolecular condensates are crucial organisers of cellular architecture and physiology. Paraspeckles are model condensates whose studies helped understand the molecular grammar governing physiological phase separation. Paraspeckles share numerous components with other condensates, e.g. splicing speckles, yet they remain separate entities. Mechanisms ensuring biocondensate autonomy whilst allowing efficient component exchange are currently unknown. Recent studies suggested that protein post-translational modifications (PTMs), that are known to fine-tune RNA-binding proteins’ phase-separating properties, can underlie these mechanisms.
Objectives:
1. Identify the paraspeckle proteins (PSPs) whose regulation by PTMs is responsible for paraspeckle autonomy.
2. Characterise the changes in paraspeckle stability, dynamics, turnover and function upon manipulation of PSPs’ PTM profile.
3. Establish the stress-dependent changes in the PSP PTMs and their role in stress-induced paraspeckle hyper-assembly and nuclear architecture remodelling.
The project will utilise a combination of quantitative mass-spectrometry, RNA in situ hybridization, immunocytochemistry, high-content and super-resolution imaging, pharmacological manipulation of cellular pathways, molecular cloning and engineered cell lines in order to better understand the regulatory potential of PTMs within the cellular condensate network. This project should close the gap between the in vitro and cellular studies of biocondensates and is well-positioned to generate novel knowledge that may drive a major cell biology rethink.
About the DTP
This studentship is offered as part of the White Rose BBSRC Doctoral Training Partnership (DTP) in Mechanistic Biology, which brings together the research of the world-class molecular and cellular bioscience centres at the White Rose universities of Leeds, Sheffield and York.
Our mission is to train excellent bio-scientists who understand how living systems work
and can innovate to address global challenges, such as the impact of climate change, a healthier old age, sustainable food production, land use and energy production.
What is on offer?
This is a core studentship for entry in October 2024.
Join us and you will receive a 4-year, funded PhD programme of research and skills training, with cross-disciplinary supervision, plus a structured programme of cohort-wide training and networking events. A highlight is the annual symposium, which is planned and delivered by students.
A unique part of your training will be the Professional Internships for PhD Students (PIPS), where you will spend three months at a host organisation of your choosing, gaining experience of work in a professional environment, and acquiring transferable skills that will be beneficial in your future career.
How to apply – Expression of Interest
Students may apply for up to three projects anywhere in the Doctoral Training Partnership (DTP). Applications will be to the DTP centrally, using an online Expression of Interest (EoI). The EoI will include:
§ CV information; not submitted separately
§ Equality, Diversity and Inclusion (EDI) data
§ Names of two referees
Deadline for EoIs is midnight Sunday 7th January 2024.
Submit EoIs using this link: https://leeds.onlinesurveys.ac.uk/white-rose-bbsrc-dtp-expression-of-interest-form
Shortlisted candidates will be required to make formal applications to the Graduate School at each institution, supplying the necessary paperwork.
Interviews will be held either Friday 2nd and Monday 5th to Friday 9th February, or Monday 19th to Friday 23rd and Monday 26th February 2024, in-person at Leeds, Sheffield and York, with a panel representing all 3 Universities. Shortlisted candidates will be notified of a specific time/date to attend. If you have applied for more than one project and are selected for interview, you will be interviewed only once.
Website link: https://www.whiterose-mechanisticbiology-dtp.ac.uk/
Funding Notes
Appointed candidates will be fully funded for 4 years:
Tax-free annual stipend at the UKRI rate. The rate for starters in 2023/24 was £18,622. (Rates for 2024/25 starters are not yet available).
UKRI tuition fees – These are paid directly to the host institution.
A Research Training and Support Grant
An allowance for Fieldwork/Conference/Travel
A Professional Internship for PhD Students (PIPS) allowance
Not all projects will be funded; the DTP will appoint a limited number of candidates via a competitive process.
References
1. An H, Elvers KT, Gillespie JA, Jones K, Atack JR, Grubisha O, Shelkovnikova TA* (2022) A toolkit for the identification of NEAT1_2/paraspeckle modulators. Nucleic Acids Research, gkac771.
2. An H, Litscher G, Watanabe N, Wei W, Hashimoto T, Iwatsubo T, Buchman VL, Shelkovnikova TA* (2021) ALS-linked cytoplasmic FUS assemblies are compositionally different from physiological stress granules and sequester hnRNPA3, a novel modifier of FUS toxicity. Neurobiol Dis. 162(105585).
3. An H, Tan J.-T., Shelkovnikova TA* (2019) Stress granules regulate stress-induced paraspeckle assembly. J Cell Biol. 218(12):4127-414.
4. Shelkovnikova TA*, An H, Skelt L, Tregoning JS, Humphreys IR, Buchman VL (2019) Antiviral Immune Response as a Trigger of FUS Proteinopathy in Amyotrophic Lateral Sclerosis. Cell Rep. 29(13):4496-4508.e4.
Jackson PJ, Hitchcock A, Brindley AA, Dickman MJ, Hunter CN.Absolute quantification of cellular levels of photosynthesis-related proteins in Synechocystis sp. PCC 6803. Photosynth Res. 2023, (3):219-245.
Lambiase G, Klottrup-Rees K, Lovelady C, Ali S, Shepherd S, Muroni M, Lindo V, James DC, Dickman MJ. An automated, low volume, and high-throughput analytical platform for aggregate quantitation from cell culture media. J Chromatogr A. 2023, 1691:463809.
Flannery SE, Pastorelli F, Wood WHJ, Hunter CN, Dickman MJ, Jackson PJ, Johnson MP. Comparative proteomics of thylakoids from Arabidopsis grown in laboratory and field conditions. Plant Direct. 2021, 5(10):e355.
Howard JD, Beghyn M, Dewulf N, De Vos Y, Philips A, Portwood D, Kilby PM, Oliver D, Maddelein W, Brown S, Dickman MJ. Chemically modified dsRNA induces RNAi effects in insects in vitro and in vivo: A potential new tool for improving RNA-based plant protection. J Biol Chem. 2022, 298(9):102311