PhD project

Supervisor: Fumiko Esashi

Centromeres are the structural regions of chromatin that serve as a platform for the kinetochore machinery assembly, hence essential for accurate chromosome segregation during cell division. Their structural and functional integrity is therefore fundamental for preventing human diseases, such as cancer.

Human centromeres comprise highly repetitive alpha-satellite DNA sequences spanning several mega-bases, although only small sections of these repetitive regions are functionally active. Curiously, centromere DNA sequences diverge extensively between closely associated species. The dichotomy between diverging centromere DNA sequences and highly conserved centromere functionality is described as the “centromere paradox” and remains enigmatic for many decades (1).

Recent works from the Esashi group provided some insights regarding the underlying mechanism, partly explaining the centromere paradox. First, centromeres are universal hotspots of DNA breakage (2). Second, the central homologous recombination (HR) repair enzyme, the RAD51 recombinase, prevents the accumulation of centromeric DNA breaks in dividing cells (3) and also in non-cancerous cells in a state of reversible growth arrest, known as quiescence (2). Finally, RAD51 assist in maintaining centromere functionality, as defined by CENP-A occupancy (2). These observations raise many new questions, however. Why do centromeres get broken during quiescence? How is RAD51 recruited to centromeres? How does RAD51 support CENP-A occupancy? Is centromeric HR truly advantageous (friend) or harmful (foe)?

This project tackles these fundamental questions by exploiting innovative and multidisciplinary experimental approaches developed uniquely in the group, including genetics, advanced light microscopy and third-generation sequencing. The project offers a unique training opportunity for students to interact with a powerful team of experts in DNA repair, recombination and chromatin.

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

Publications

• Henikoff, S., Ahmad, K. & Malik, H. S. (2001) The centromere paradox: stable inheritance with rapidly evolving DNA. Science 293, 1098-1102,
• Saayman X et al (2023) Centromeres as universal hotspots of DNA breakage, driving RAD51-mediated recombination during quiescence. Mol Cell 83, 523–538
• Wassing I.E. et al. (2021) The RAD51 recombinase protects mitotic chromatin in human cells Nat Commun. 12, 5380.