PhD project

Supervisor: Fumiko Esashi

Centromeres are specialised chromatin domains that serve as essential platforms for kinetochore assembly, thereby ensuring accurate chromosome segregation during cell division. Their structural and functional integrity is critical for maintaining genome stability and preventing human diseases, including cancer.

In humans, centromeres are composed of highly repetitive alpha-satellite DNA sequences that span several megabases. Intriguingly, these sequences vary significantly even between those from different chromosomes. This striking contrast between the divergence of centromeric DNA and the conservation of centromere function is known as the “centromere paradox,” a long-standing enigma in chromosome biology (1).

Recent studies from the Esashi group have begun to shed light on the mechanisms underlying this paradox. First, centromeres have been identified as universal hotspots for DNA breakage (2). Second, the homologous recombination (HR) repair enzyme RAD51, along with its key regulators BRCA2 and PALB2, plays a significant role in protecting centromeres in dividing cells (3, 4). Third, this protective role of RAD51 extends to non-dividing quiescent cells, which are in a reversible state of growth arrest (2). Finally, RAD51 is directly involved in preserving centromere functionality in both dividing and quiescent cells (2). These findings raise several compelling questions: Why are centromeres prone to breakage during quiescence? How is RAD51 recruited to centromeres? In what ways does RAD51 support centromere function? And ultimately, is centromeric HR a protective mechanism (friend) or a source of instability (foe)?

This project aims to address these fundamental questions using a suite of innovative, multidisciplinary approaches uniquely developed within the group. These include advanced genetic tools, high-resolution light microscopy, and third-generation sequencing technologies. The project also offers an exceptional training environment, enabling students to collaborate with a dynamic team of experts in DNA repair, recombination, and chromatin biology.

Informal inquiries about the project are welcome and should be made to: fumiko.esashi@path.ox.ac.uk

Keywords:

• Biochemistry, Bioinformatics, Biomedical Engineering, Biophysics, Biotechnology, Cancer / Oncology, Cell Biology / Development, Evolution, Genetics, Molecular Biology

Publications

1. Henikoff, S., Ahmad, K. & Malik, H. S. (2001) The centromere paradox: stable inheritance with rapidly evolving DNA. Science 293, 1098-1102,
2. Saayman X et al (2023) Centromeres as universal hotspots of DNA breakage, driving RAD51-mediated recombination during quiescence. Mol Cell 83, 523–538
3. Wassing I.E. et al. (2021) The RAD51 recombinase protects mitotic chromatin in human cells Nat Commun. 12, 5380.
4. Graham E. et al. (2025) The homologous recombination factors BRCA2 and PALB2 interplay with mismatch repair pathways to maintain centromere stability and cell viability. Cell Reports. 44, 115259.