DNA damage response (DDR) and repair play critical roles in influencing the efficiency and sensitivity of many cancer treatments. The large amount of DNA damage generated during chemo/radiotherapy can kill cancer cells, which are under high replication stress. Hence, further inhibition of DDR and repair can enhance treatment outcome. The differences between DDR and repair function in normal and tumour cells creates an exciting therapeutic opportunity for the development of a new generation of targeted cancer drugs through a principle called synthetic lethality. However, intrinsic or acquired resistance to these drugs occurs in many patients causing a lack response or tumour regrowth. Therefore it is essential to understand the mechanisms of DDR and repair in order to classify various functions that influence cancer treatments.
Conventional methods of knockdown/out genes or genetic mutants do not provide detailed molecular understanding of how a specific protein interaction is responsible for its unique function. This project is going to solve this problem by generating a group of small protein molecules (Affimer, function like antibody but with much smaller size) that can inhibit particular domains of DDR complexes to provide a molecular understanding of how these complexes influences the sensitivity for cancer cells from each type of cancer treatments. These Affimer protein tools will also provide the opportunities for modulating the function of DNA repair protein and super-resolution imaging in cancer cells.
This studentship will deliver interdisciplinary training in protein biochemistry, and molecular, structural and cellular biology. The technical skills will include isolation of Affimers through phage display (a technique recognised in Nobel prize Chemistry 2018), cloning, protein expression/purification, biophysical/biochemical methods (e.g. ITC, SPR and EMSA), structural methods (X-Ray/NMR) and cellular assays. These trainings will equip student to pursue cutting edge interdisciplinary research at the life sciences interface. Moreover both the primary and secondary supervisors’ laboratories will train students to develop the mind-set and communication skills needed to pursue both precise and quantitative research .
Supervisors and laboratory environment
Both supervisors will supervise and stimulate the student to establish good practice of research skills, learn cutting edge techniques and obtain the latest research knowledge.
Dr Qian Wu (Primary supervisor) works in DNA repair field and specialises at characterization of the structural mechanism of human DNA repair pathways for double-strand breaks.
- Lab website:http://qianwulab.org and https://biologicalsciences.leeds.ac.uk/biological-sciences/staff/1136/dr-qian-wu
- Twitter: @qianqian5000
- Contact Dr Wu ([email protected]
) for more information about this project.
Dr Darren Tomlinson (Secondary supervisor) specialises using Affimer proteins to understand how proteins function within cells, especially a range of proteins involved in cancer biology and has successfully used Affimers for blocking protein domain function.
- Lab website: https://biologicalsciences.leeds.ac.uk/molecular-and-cellular-biology/staff/145/dr-tomlinson
- Twitter: @Tomlinson_lab
We are a group of young scientists consisting of over 20 PhD student, PDRAs and technicians, who are driven and passionate about science and its application towards human health. We created an interactive and friendly research environment with diversity and inclusion to support the development of individual group members and also form a strong force as a team to develop tools for studying important biological question.
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website: http://www.dimen.org.uk/