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Title: Novel variants of the DNA damage checkpoint protein Cds1 in Schizosaccharomyces pombe
Author: Fletcher, Jessica Frances
ISNI:       0000 0004 6352 4039
Awarding Body: Prifysgol Bangor University
Current Institution: Bangor University
Date of Award: 2017
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In the model organism Schizosaccharomyces pombe, the Cds1 (checking DNA synthesis 1) kinase is activated at the S-phase checkpoint upon stalling of the replication fork during DNA synthesis. Under normal conditions (300C), the role of the full-length protein kinase is to activate downstream processes resulting in mitotic arrest,protection of the stalled replication fork, and prevention of continued DNA replication in an unfavourable environment. In this way, Cds1 acts to ensure the reversible arrest of DNA synthesis. However, under stress conditions such as raised temperature or specific DNA damaging drugs, shorter variants of this protein kinase are rapidly expressed. Initial experimentation revealed the origin of the predominant variant, named Cds1-B, as the internal translation initiation site Methionine 159. The expressed protein is N-terminally truncated, missing amino acids residues 1-158, and therefore lacking the regulatory SQ/TQ and FHA domains whilst retaining the kinase domain. Absence of these regulatory regions suggests that this variant is free to act outside of the chromatin environment to fulfil roles different to that of its full-length counterpart, however it is unlikely to be active as a kinase as it is unable to participate in the model of activation currently proposed in the literature. Experimentation in this project was aimed at elucidating the role of this Cds1-B variant through analysis of drug sensitivity and checkpoint control efficacy, and evaluation of kinase activity. Current literature and results discussed here suggest an interesting hypothesis in which variants are expressed in response to specific genotoxic stresses in order to self-regulate kinase activity and selectively mediate cellular response either by the DNA replication checkpoint effector Cds1 or the DNA damage checkpoint effector Chk1. Mediation of effector kinase action is a promising avenue for cancer treatment, and with a potential Cds1-B homologue for human Chk2 identified (splice variant isoform 13), gaining a greater nderstanding of these variant mechanisms in yeast will aid the development of new therapeutic interventions.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available