University of Dundee

ROUSE, John: Targeting DNA repair pathways for personalized cancer treatment

Our chromosomes are frequently subjected to insults that damage DNA, and if not rectified the resulting DNA lesions can cause genome mutations and human disease. Mutations in the major DNA repair pathways – such as homologous recombination (HR) – cause heightened susceptibility to a range of human cancers. These HR-defective cancers become highly dependent on minor, accessory DNA repair pathways that are not required in normal tissues, an example of what is often referred to as “synthetic lethality”. These minor DNA repair pathways represent a vulnerability in certain cancers, and switching them off represents a new way of treating certain cancers, such as those caused by loss of HR, without affecting normal tissue. The BRCA1 or BRCA2 genes encode HR proteins, and mutations in these genes cause a range of cancers. The project on offer will explore a new pathway that becomes essential in cells with mutations in the BRCA genes and will explore the therapeutic potential of the pathway. This study may ultimately lead to new treatments for cancers caused by mutations in HR genes. A range of lab techniques will be involved including CRISPR-mediated human genome editing, confocal microscopy, and analysis of chromosomal recombination and DNA repair in cells.

References

Ashworth, A. et al, Nat. Rev. Clin. Oncol. 15, 564-576.

Lord, C. et al, Science 355, 1152-1158

Castor, D. et al, Mol. Cell 52, 221-233.

Feeney, L. et al, Mol. Cell 66, 610-621. 

Alvarez-Alquilon, A. et al, Mol. Cell 78, 1152-1165.

Eligibility