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Title: Characterisation of a methyl-CpG binding domain protein in Caenorhabditis elegans and mammals
Author: Carr, Michael J.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1999
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The recently sequenced genome of the model organism C. elegans was found to contain a gene that potentially encoded a protein containing a methyl-CpG binding domain and intriguingly, two motifs present in chromatin-associated transcriptional regulators - the PHD-zinc finger and bromodomain. The gene was given the standard name pbm-1 for PHD-zinc finger, bromodomain and MBD gene-1. The MBD of pbm-1 was found to be highly homologous to a human EST suggesting evolutionary and functional conservation of this domain. A mouse cDNA, mPBM1 was identified that encoded a protein with the same modular organisation of motifs as the C. elegans pbm-1 protein. The aim of this project was the characterisation of this gene family using a cross-species approach that exploited the advantages particular to the nematode and mammalian systems. The MBDs of pbm-1 and mPBM1 did not associate with methylated sequences in a series of in vitro binding studies. These findings do not rule out the possibility that the MBDs mediate binding to other covalent modifications of DNA or specific sequence targets. In support of the in vitro findings, the mPBM1 protein did not associate with the heavily methylated mouse major satellite when fused to GFP and was found to localise in a diffuse, granular pattern in the nucleus. Furthermore, the MBD of mPBM1 was dispensable for the spatial localisation of the protein. Deletion of a C-terminal element encompassing the PHD-zinc finger and bromodomain regions abolished the wild type localisation in mouse nuclei. The PHD-zinc finger has been identified in a number of chromosomal translocations involved in acute leukaemias suggesting that deregulation of normal expression contributes to the transformation phenotype. The hPBM1 gene was physically mapped to chromosome 2q23 in a region found deleted and rearranged in leukaemias.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available