Dr G Bernardes, Prof T Kouzarides
No more applications being accepted
Competition Funded PhD Project (Students Worldwide)
About the Project
This PhD position in the Onco-Innovation Programme provides a unique opportunity for a highly motivated individual to conduct research within a multidisciplinary group of chemists, biologists and physicists, using state-of-the-art technologies and methods.
The student will be supervised daily in the Bernardes lab by Dr Tiago Rodrigues, an experienced researcher with expertise in computational and medicinal chemistry.
Project Description
Cancer remains a leading cause of death and morbidity worldwide, despite extensive basic and clinical research efforts dedicated to finding ways to control tumour growth, and cure diseased tissues. The identification of small molecules with novel mechanisms of action and interfering with untapped biology is thus urgently sought after. N6-methyladenosine (m6A) is the most abundant internal modification of mRNA and regulates a plethora of events. Wang et al.1 have recently identified that the methyltransferase-like 3 (METTL3) and METTL14 regulate such events. Importantly, functional activity of this complex is crucial for cancer progression, survival and invasion.2
Mechanistically, loss and gain of function assays show that both transferases act synergistically to control m6A formation.1,3 Hence, proper molecular recognition between METTL3 and METTL14 is key. A high-resolution X-ray crystal structure of the METTL3-METTL14 complex has recently been reported.4 We hypothesize that the disruption of the METTL3-METTL14 interaction leads to important phenotype changes in cancer cells, e.g. apoptosis, with translational potential to the clinic. To interrogate the biology underlying the METTL3-METTL14 complex, we aim to identify small molecule probes interfering with this interaction and, consequently, with RNA methylation.
To read more please visit Cambridge Cancer Centre website: http://www.cambridgecancercentre.org.uk/studentships
Funding Notes
This is one of 20 projects being advertised by the Cambridge Cancer Centre, a partnership between the University of Cambridge, Cancer Research UK and Cambridge University Hospitals NHS Foundation Trust bringing together academic researchers, clinicians, and industry collaborators in the Cambridge area. Up to 10 awards (supporting both clinical and non-clinical students) will be available. Non-clinical studentships fund the University Composition Fee (Home/EU rate), provide a consumables budget, and a stipend, currently £19,000 per annum. Clinical research fellowships cover salary costs for the fellow, a consumables budget, and funding for the University Composition Fee (at staff rate) for three years.
References
1. Wang Y, Li Y, Toth JI, Petroski MD, Zhang Z, Zhao JC. N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nat Cell Biol. 2014 Feb;16(2):191-198.
2. Lin S, Choe J, Du P, Triboulet R, Gregory RI. The m6A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells. Mol Cell. 2016 May 5;62(3):335-345.
3. Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L, Jia G, Yu M, Lu Z, Deng X, Dai Q, Chen W, He C. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol. 2014 Feb;10(2):93-95.
4. Wang X, Feng J, Xue Y, Guan Z, Zhang D, Liu Z, Gong Z, Wang Q, Huang J, Tang C, Zou T, Yin P. Structural basis of N6-adenosine methylation by the METTL3-METTL14 complex. Nature. 2016 May 25;534(7608):575-578.
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