The centromere is a region of chromatin that serves as a platform for the kinetochore machinery assembly, hence is essential for accurate chromosome segregation during cell division. Human centromeres are characterised by highly repetitive alpha-satellite DNA sequence, encompassing several mega-bases. This property allows for the robustness of centromere function in chromosome segregation. However, centromeres are also difficult-to-replicate and experience substantial mechanical stress during chromosome segregation, poising centromeres as prime candidates for sites of DNA breakage. Indeed, chromosomal breakage and translocation at centromeres are often found in cancer cells.
Recent works from the Esashi group revealed that the central homologous recombination (HR) repair enzyme, the RAD51 recombinase, prevents centromere fragility in cells exposed to mild replication stress (1, 2, 3). However, the full picture of the mechanism by which RAD51 acts at centromeres is unclear. Further, while centromeres have been known to be highly recombinergic and rapidly evolving, it remains enigmatic whether HR at centromeres is truly advantageous (friend) or harmful (foe).
This project tackles this fundamental question by exploiting innovative experimental approaches that enables the direct assessment of the level of DNA damage at centromeres in human cells. The study will use multidisciplinary approaches, such as biochemistry, genetics, advanced light microscopy and next- or third- generation sequencing. The project offers a unique training opportunity for student to interact with a powerful team of experts in the fields of DNA repair, recombination and replication and cell division.