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Title: Protein-protein interactions underlying damage checkpoint activation in S. pombe
Author: Wardlaw, Christopher
ISNI:       0000 0004 5359 9715
Awarding Body: University of Sussex
Current Institution: University of Sussex
Date of Award: 2014
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DNA damage can lead to the accumulation of mutations and diseases such as cancer. It is therefore integral for cells to identify this damaged DNA and promote its repair. To carry out this function eukaryotic cells have evolved signal transduction pathways known as the DNA structure checkpoints. Much of the molecular mechanism underlying these pathways is still far from understood. The work in this thesis uses the model organism Schizosaccharomyces pombe to investigate these mechanisms, with a particular focus on the TopBP1 homolog Rad4. TopBP1 plays an essential scaffolding role in the initiation of DNA replication, but is also a key protein in the DNA structure checkpoints. It has previously been shown in metazoans and budding yeast to stimulate the kinase activity of ATR, via its ATR Activation Domain (AAD), an early event in checkpoint activation. The work presented in here, along with initial work carried by previous members of the Carr Laboratory; Su-Jiun Lin and Valerie Garcia, shows that the Rad4TopBP1 AAD acts in a chromatin dependent pathway to amplify the checkpoint signal in G1/S-phase, where DNA resection is limited. A second AAD is also identified in the checkpoint clamp protein Rad9, which acts redundantly with the Rad4 AAD. As well as its AAD function, Rad4 also plays a scaffolding role in the DNA structure checkpoint pathways. The work in this thesis, in collaboration with the Laurence Pearl and Li Lin Du laboratories, identifies the molecular mechanism of the interaction between Rad4 and the mediator protein Crb253BP1. It is shown that sequential phosphorylation of Crb2 by Cdc2CDK is required for the interaction with BRCT domains 1 and 2 of Rad4 and checkpoint activation. It is also shown that Rad4 most likely does not interact with Mrc1 or Slx4 in the S. pombe checkpoint pathways.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD0415 Biochemistry