Understanding the Complexities of Non-Homologous End Joining (NHEJ) DNA Repair

Open to UK applicants only

Supervisors:

• Dr Amanda Chaplin ac853@leicester.ac.uk 
• Professor Thomas Schalch thomas.schalch@leicester.ac.uk

Project description:

This PhD project aims to investigate the structure and function of protein complexes involved in the DNA repair mechanism known as non-homologous end joining (NHEJ), using primarily cryo-electron microscopy (cryo-EM). NHEJ is one of the primary pathways responsible for repairing double-strand breaks (DSBs) in DNA—lesions that, if left unrepaired, can lead to genomic instability, cell death, or cancer.

Our lab has recently characterised several large, multicomponent assemblies that play crucial roles in this repair process. Building on these findings, the project will delve into the molecular architecture and regulatory dynamics of these complexes, with a focus on understanding the formation and functional implications of alternative assembly states.

By uncovering the intricacies of NHEJ regulation, this research will contribute to a more detailed understanding of DNA repair pathways and their potential as therapeutic targets. Inhibition of NHEJ has already shown promise as a strategy to enhance the efficacy of chemotherapy and radiotherapy in cancer treatment. This project will therefore not only advance fundamental knowledge but also inform the development of novel therapeutic approaches.

References

• “Structural and functional insights into the interaction between Ku70/80 and Pol X family polymerases in NHEJ”. Frit, P, Amin, H, Zahid, S, Barboule, N, Hall, C, Matharu G, Hardwick SW, Chauvat, J, Britton, S, Chirgadze DY, Ropars, V, Charbonnier JB, Calsou, P, Chaplin AK. 2025. Nature Comms
• “PAXX binding to the NHEJ machinery explains functional redundancy with XLF”. Dahan MSE, Kefala-Stravridi A, Frit P, Hardwick SW, Chirgadze DY, Oliviera TMD, Britton, Barboule N, Bosssaert M, Pandurangan AP, Meek K, Blundell TL, Ropars V, Calsou P, Charbonnier JB, Chaplin AK. Sciences Advances.
• “Structural and functional basis of inositol hexakisphosphate stimulation of NHEJ through its interaction with Ku70-Ku80”. Kefala-Stavridi A, Gontier A, Morin V, Frit P, Barboule N, Racca C, Jochhe S, Morten MJ, Andreani J, Guerois R, Rak A, Legrand P, Ropars V, Bourand-Plantefol A, Hardwick SW, Chirgadze DY, Davey P, Oliveira TMD, Rothenberg E, Britton S, Calsou P, Blundell TL, Varela PF, Chaplin AK, Charbonier JB. Nucleic Acids Research.
• “Cryo-EM of NHEJ super complexes reveal new insights into DNA repair”. Chaplin AK, Hardwick SW, Kefala Stavridi A, Liang S, Chirgadze, DY, Blundell, TL. 2021.– Molecular Cell.
• “Dimers of DNA-PK create a stage for DNA-double strand break repair” Chaplin AK, Hardwick SW, Liang S, Kefala Stavridi A, Hnizda A, Cooper LR, Maia De Oliveira T, Chirgadze, DY, Blundell, TL. Nat Struct Mol Biol. 2021. 1. 13-19.

Closing date for application is 16 July 2025. 

Interview date: Friday 18 July 2025 (via Teams).  If you are invited to interview, you will be contacted on or before 17 July.