Structure and molecular function of the DREAM complex in gene expression programs of cellular quiescence
This PhD project is proposed for a candidate with a strong interest in the cell cycle. The cell cycle is the fundamental biological process where the cell coordinates chromosome replication and segregation with cell growth and division. In response to internal/external cues individual metazoan cells can exit from the cell cycle. Cell cycle exit is reversible during cellular quiescence, a process essential for stem cell maintenance and thereby for tissue regeneration. Quiescent tumour stem cells are present in early cancer metastasis, a phenomenon called “cancer dormancy”, which causes failure of common therapies targeting the cycling cells.
Progression through the cell cycle is orchestrated by a complex interplay of cell cycle regulators such as the cyclins, which are finely regulated at the level of gene expression, protein synthesis, degradation and phosphorylation. The cyclins activate the cyclin-dependent kinases, which promote cell cycle progression.
During quiescence, cyclin gene expression is repressed by the 8-subunit DREAM complex, a master coordinator of the cell cycle dependent gene expression. DREAM assembles at cell cycle activators gene promoters and promotes transcriptional repression. The assembly mechanism of the DREAM complex and its molecular interactions with chromatin, which are both critical to understand its molecular mechanism of gene repression, are unknown or poorly characterized.
This project focuses on dissecting the molecular mechanisms of DREAM-mediated cell cycle regulation by using a combination of protein complex reconstitution, biochemical analysis and structural characterization by cryo-electron microscopy (cryo-EM).
Disruption of the cell cycle is one of the main features of cancerous cells. The pathway involving the DREAM complex is misregulated in several cancer types. Understanding the molecular mechanism of DREAM-mediated cell cycle regulation will contribute to (i) understanding the molecular biology of quiescence and to (ii) designing novel anti-cancer drugs to be used in more effective therapies targeting both cycling and quiescent tumour cells.
Download a PDF of the complete project proposal: https://d1ijoxngr27nfi.cloudfront.net/docs/default-source/studying-at-the-icr/yap_bliss_icr-studentship---website.pdf?sfvrsn=f1e55a69_2
Candidate profile Candidates must have a first class or upper second-class honours BSc Honours/MSc in Biology, Biochemistry or Chemistry, and proven experience in wet lab work. Experience in protein biochemistry and/or structural biology would also be desirable.
How to apply Full details about these studentship projects, and the online application form, are available on our website, at: www.icr.ac.uk/phds
Applications for all projects should be made online. Please ensure that you read and follow the application instructions very carefully.
Applications close 11:55pm UK time on Sunday 17th November 2019
Please apply via the ICR vacancies web portal: https://apply.icr.ac.uk/
Students receive an annual stipend, currently £21,000 per annum, as well as having tuition fees (both UK/EU and overseas) and project costs paid for the four-year duration. We are open to applications from any eligible candidates and are committed to attracting and developing the best minds in the world.