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Investigating the mechanism maintaining centromere integrity.


Sir William Dunn School of Pathology

Dr F Esashi , Dr U Gruneberg Friday, January 08, 2021 Competition Funded PhD Project (Students Worldwide)

About the Project

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.

Significantly, works from the Esashi group revealed that one of essential DNA repair proteins, the RAD51 recombinase, prevents centromere fragility, in a manner dependent on its phosphorylation by polo-like kinase 1, a central mitotic kinase which is enriched at centromeres (1, 2, 3). In line with this finding, emerging evidence indicates the enrichment of several repair proteins at centromeres (4). However, the full picture of the mechanism maintaining centromere integrity remains a major question in the field.

This project tackles this fundamental question by exploiting a newly developed system that enables the identification of factors that accumulate at centromeres upon the induction of local damage. The study will be followed by the characterisation of identified factors using multidisciplinary approaches, such as biochemistry, genetics and microscopic analysis. 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 (Esashi) and centromere and kinetochore biology (Gruneberg).

Funding Notes

4 Year DPhil Prize Studentships cover full University fees, a tax free enhanced stipend of ~£17,285 pa, and up to £5,300 pa for research costs and travel. The competition is open to applicants from all countries. See View Website for full details and to apply.

References

1. Yata et al. (2012) PLK1 and CK2 act in concert to regulate RAD51 during DNA double strand break repair Mol Cell 45:371-83.
2. Yata et al., (2014) BRCA2 coordinates the activities of cell-cycle kinases to promote genome stability Cell Reports 7,1547-1559
3. Wassing I.E. et al. (2020) The RAD51 recombinase protects mitotic chromatin in human cells BioRxiv (https://doi.org/10.1101/2020.08.11.246231)
4. Gao et al., (2018) C-BERST: defining subnuclear proteomic landscapes at genomic elements with dCas9–APEX2. Nature Methods 15, 433–436
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