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Genome Diversification in Cancer and Adaptive Immunity

   Weatherall Institute of Molecular Medicine

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  Assoc Prof R Chapman  No more applications being accepted  Self-Funded PhD Students Only

About the Project

Genomic instability (GI) is a hallmark of cancer that plays a central role in its initiation and development. GI can arise as a result of germline and somatic mutations that compromise a cell’s ability to accurately sense, signal or repair DNA damage. GI can also arise as a result of errors in chromosome segregation during mitosis, or when chromosome breakage events result in the transmission of chromosome rearrangements, and/or gains and losses to daughter cells during cell division. These catastrophic events are not only linked to tumour initiation, they also play a central role in cancers ability to evolve and acquire new aggressive traits, such as the ability to metastasize, or become resistant to anti-cancer therapies. However, in some specialised cell types, genome rearrangements must occur as programmed, highly orchestrated events, where they function to bring about genetic diversity: the B and T lymphocytes of our immune systems deliberately induce and repair DNA breaks in a mutagenic fashion to diversify antibody and antigen receptor encoding genes. Research in the Chapman laboratory aims to better understand the biological pathways that allow for genome diversification as a physiological process, and those that lead to GI in cancer. We also work towards devising strategies to exploit the GI-driving pathways as vulnerabilities to selectively kill cancer cells.

DPhil projects will be tailored to complement one of the following research topics in the lab: 

1.     Genetic recombination in lymphocyte development, longevity and malignancy – In dissecting mutagenic DNA repair mechanisms that are vital for lymphocyte development and immune-diversification, the laboratory has also revealed mechanisms that trigger the onset of familial breast and ovarian cancers.

2.     DNA double-strand break repair pathway choice in genome maintenance and cancer prevention - The laboratory has a long-standing interest in the context-specific regulation of accurate and mutagenic DNA double-strand break repair systems. We are particularly interested in the BRCA1 tumour suppressor pathway, its contribution to homologous recombination (HR), and suppression of toxic non-homologous end-joining (NHEJ). 

3.     Exploiting GI driving mechanisms in the treatment of cancer – Loss or deregulation of a genome maintenance activity in cancer often comes at a cost. The laboratory uses molecular genetics and screening approaches to identify genetic vulnerabilities intrinsic to GI-driven cancers, in the hope of improving the treatment of cancer.

Interdisciplinary by design, DPhil projects will utilise a broad range of cutting-edge molecular and genetic technologies, and will foster interactions with multiple labs in the WIMM. Experimental approaches in the lab include advanced molecular biology, quantitative proteomics, quantitative and super-resolution imaging, CRISPR-Cas9 genome editing, structural biology and transgenic mouse models. The laboratory also utilises genome-wide screening technologies, and is developing methods to analyse the repair of endogenous DNA breaks on a genome-wide level. Training opportunities at the WIMM also exist to develop expertise in basic and advanced bioinformatics.

Additional supervision will be provided by Professor Ketan Patel.

Students will be enrolled on the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence, and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.


1 Becker, J. R. et al. Nature, 2021 - https://doi.org/10.1038/s41586-021-03776-w
2 Yeow, Z.-Y. et al. Nature, 2020 - https://doi.org/10.1038/s41586-020-2690-1
3 Nakamura, K. et al. Nature Cell Biology, 2019 - https://doi.org/10.1038/s41556-019-0282-9
4 Becker, J. R. et al. Nature Communications, 2018- https://doi.org/10.1038/s41467-018-07855-x
5 Ghezraoui, H. et al. Nature, 2018 - https://doi.org/10.1038/s41586-018-0362-1
6 Cuella-Martin, R. et al. Molecular Cell, 2016 - https://doi.org/10.1016/j.molcel.2016.08.002
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