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Title: Roles of BRCA1 and BRCA2 in DNA replication and genome stability
Author: Zimmer, Jutta
ISNI:       0000 0004 6498 9970
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2017
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Genomic instability is a hallmark of cancer. The tumour suppressors BRCA1 and BRCA2 play key roles in genome integrity by promoting homologous recombination DNA repair and replication fork stability. Deficiency in these functions has been described as the Achilles heel of BRCA-defective tumours. This provides an important rationale for further exploring the roles of BRCA1 and BRCA2 in DNA replication and genome stability. G-quadruplexes, alternative DNA structures formed by guanine-rich single- stranded DNA, represent natural replication fork barriers. This study demonstrates that treatment with the G-quadruplex-stabilising compound pyridostatin selectively decreases viability of BRCA1- and BRCA2-deficient cells by inducing replication stress and DNA damage. Furthermore, this work identifies a new role of the Fanconi anaemia protein FANCD2 in limiting replication fork progression and genomic instability in human cancer cells lacking BRCA2. This function of FANCD2 is vital for BRCA2-deficient cell survival and affects treatment responses. Finally, the data presented here reveal a synthetic lethal interaction between MRE11 nuclease and BRCA2. Characterisation of a novel chemical MRE11 nuclease inhibitor with activity on 2D and 3D cell culture models for BRCA2 deficiency highlights the clinical relevance for the use of MRE11 inhibitors for targeting BRCA2-deficient tumours. In summary, this report describes novel roles of BRCA1 and BRCA2 relevant for selective targeting of BRCA-deficient tumour cells.
Supervisor: Tarsounas, Madalena Sponsor: Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available