Henry Wellcome Building of Genomic Medicine
The Chromosome Dynamics Group
We are based in the Wellcome Trust Centre for Human Genetics, in the Nuffield Department of Medicine at the University of Oxford (and in the Department of Zoology at the University of Cambridge). We study the processes that occur at replications forks and in replication factories in mammalian cells. These are likely to be physical cellular locations where the genome instability arises that can lead to cancer and other disorders. Cells have to coordinate a large number of activities at each replication fork, and this seems to involve the key replication protein PCNA that acts as a sliding clamp to recruit enzymes and regulators of DNA replication to the right place at the right time. We are particularly interested in processes that ensure the maintenance of genetic and epigenetic stability during DNA replication, but we will be looking also at the origins of chromosomal alterations: copy number variations and translocations, and the relationship between these, replication timing and the three dimensional organisation of the nucleus.
Projects in the lab include:
- Determination of the full complement of PCNA interactors, and how this is modified upon replication stress (Simon Cooper – BBSRC funded). This project uses affinity purification and high throughput bimolecular fluorescence complementation (BiFC) screens to identify and characterise novel PCNA interactors.
- Dynamics of PCNA interactions at replication forks (Shiphali Shetty – CRUK funded). This project uses fluorescence resonance energy transfer (FRET) to monitor protein-protein interactions in real time in living cells.
- Structure-function of PCNA in replication and repair (Helen Chambers – CRUK funded). This project is investigating how different mutations of PCNA affect its role in diverse cellular processes.
- PCNA involvement in epigenetic inheritance (Diana Vallejo – funded by the Generalitat Valenciana). This project uses a combination of protein biochemistry and Drosophila genetics to investigate the role of PCNA in coordinating the transmission of epigenetic states during DNA replication.
- Substrate identification for protein methyltransferases (Lucie Maingot - funded by the Cambridge Cancer Centre (in collaboration with Chris Abell)). This project involves the design and synthesis of S-adenosyl methionine derivatives to label methylated proteins in vitro and in vivo.
- Physical structure of replication foci and its relationship with genome stability (Michal Gdula – funded by the Wellcome Trust). This project is investigating how the three-dimensional organisation of the nucleus affects the replication program and the formation of chromosome translocations.
The non-canonical SMC protein SmcHD1 antagonises TAD formation and compartmentalisation on the inactive X chromosome
Gdula MR. et al, (2019), Nature Communications, 10
CRISPR-Cas9 Causes Chromosomal Instability and Rearrangements in Cancer Cell Lines, Detectable by Cytogenetic Methods.
Rayner E. et al, (2019), The CRISPR journal
ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair
Wells D. et al, (2019)
Migration through physical constraints is enabled by MAPK-induced cell softening via actin cytoskeleton re-organization.
Rudzka DA. et al, (2019), Journal of cell science, 132
The p38α Stress Kinase Suppresses Aneuploidy Tolerance by Inhibiting Hif-1α
Simões-Sousa S. et al, (2018), Cell Reports, 25, 749 - 760.e6