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Title: Functional analysis of the methyl-CpG-binding DNA glycosylase MBD4
Author: Millar, Catherine Bridget
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2002
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The methyl-CpG-binding domain protein MBD4 can bind to methylated DNA and has glycosylase activity against thymine or uracil mismatched with guanine, preferentially within a CpG site (Hendrich et al., 1999). This particular combination of activities indicates that MBD4 may be involved in the recognition and repair of deamination-induced mismatches at CpG sites. A prediction of this model is that the number of C:G-T:A mutations would be elevated in the absence of MBD4. This hypothesis has been tested by the use of an in vivo mouse mutational assay to compare wild-type and MBD4-deficient animals. Analysis of the mutational status of these mice shows that MBD4-deficiency markedly increases the incidence of C:G-T:A mutations at CpG sites in vivo, thus demonstrating a role for MBD4 in the initiation of repair at deamination-induced G-T mismatches. Since a DNA repair defect can predispose to tumour formation, the consequences of MBD4 deficiency in relation to tumour formation were also examined. The data indicate that MBD4 acts as a tumour supressor in the intestine. A separate avenue of investigation has been to examine whether MBD4 acts alone or with partner proteins. Two-hybrid screening in yeast identified the mismatch repair protein MLH1, the kinase ZIP, and a novel protein as potential partners of MBD4. The possible biological roles of the interaction of MBD4 with these proteins have been probed using biochemical assays. In summary, the work presented in this thesis demonstrates that MBD4 acts in vivo to initiate repair at deamination-induced mismatches. In addition, the interactions of MBD4 with ZIP kinase, as well as its role in tumour suppression in the intestine indicate that this protein may have other, previously undescribed functions.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available