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Title: Understanding the role of the TOPBP1 and BLM interaction in promoting genome stability
Author: Smethurst, Elizabeth Grong
ISNI:       0000 0004 7232 7213
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2017
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The ability to sense, respond to and repair DNA damage is essential in normal development and survival of an organism. A number of human congenital syndromes are associated with mutations in pathways involved in the DNA damage response, including Seckel and Bloom syndromes. Such diseases are often characterised by developmental abnormalities and cancer, emphasising the importance of gaining a deeper understanding of the mechanisms underlying these pathways. The protein kinase ATR, mutated in Seckel syndrome, is a critical mediator of the intra S-phase checkpoint in response to replicative stress. ATR activation is a multistep process that requires its interaction with TOPBP1. Recently published data identified an interaction between TOPBP1 and the BLM helicase. This interaction is dependent on the phosphorylation of the conserved serine 304 of BLM and mutation of this residue results in genome instability. However, exactly how TOPBP1-BLM interaction protects the genome remains unclear. The findings presented in this thesis demonstrate that DT40 cells expressing the BLM S251A mutant are defective in activation of the ATR kinase upon DNA damage. In line with this, these cells display reduced CHK1 phosphorylation, increased origin firing and unreliable replication fork restart. Importantly, these phenotypes could be rescued by fusing the ATR activating domain of TOPBP1 to the mutated BLM. Furthermore, results from BLM-deficient human cell lines demonstrate similar phenotypes. Thus, this data establishes a non-enzymatic role for the BLM helicase in promoting genome stability via activation of the ATR kinase. This may help in explaining why many Bloom syndrome patients display many of the same symptoms as ATR-Seckel patients, including short stature and microcephaly.
Supervisor: Niedzwiedz, Wojciech ; McHugh, Peter Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available