Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.542450
Title: Dinucleotide TG repeats and 5' splice site definition
Author: Passoni, Monica
ISNI:       0000 0004 2712 189X
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2011
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Abstract:
During the pre-mRNA splicing process introns are removed and exons joined together in the resulting mature mRNA, which is then exported to the cytoplasm and translated into proteins. Several motifs in the nucleotide sequences near the exon-intron boundaries are required for proper exon definition including the 3' and 5' splice site consensus sequences (3'SS and 5'SS), which recruit basic splicing factors. In addition, auxiliary splicing regulatory elements, located in the upstream or downstream region of an exon, further influence exon recognition through the recruitment of additional binding proteins. This study shows that intronic UG repeat elements in proximity of the 5'SS of an exon can function as splicing regulatory elements, generally enhancing the inclusion of the upstream exon in the final mRNA through the recruitment of UG repeats-binding proteins. In particular, the strength of the 5'SS consensus sequence affects this UG repeats-mediated splicing regulation. Furthermore, this study reveals that the UG repeats-binding protein TDP-43 acts as splicing modulator either activating of inhibiting the splicing events in different minigene systems. In fact, in presence of a disease-causing mutation at the 5' end of the BRCA1 exon 12 TDP-43 enhances exon inclusion, acting as splicing enhancer. Alternatively, overexpression of TDP-43 can exert an inhibitory effect on splicing by promoting exon skipping in two newly identified TDP-43 target exons (RXRG exon 7 and ETF1 exon 7). In conclusion, this study provides positive proof of concept that UG repeats located in the downstream region of poorly defined exons help 5'SS definition. Additionally, the study characterizes the role of TDP-43 in various splicing systems presenting the UG repeat-binding sites, with the practical application of evaluating a putative splicing-affecting pathological mutation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.542450  DOI: Not available
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