Cell cycle-dependent regulation of the human RNA cap methyltransferase (RNMT)

<br/>The N-7 methylguanosine cap structure is conserved from yeast to man. It is essential for cell proliferation as it influences several steps in eukaryotic gene expression including transcription, pre-mRNA processing, RNA export and translation. The N-7 methylguanosine cap is added co-transcriptionally to RNA pol II transcripts. In mammals, two enzymes catalyse the synthesis of the N7-methylguanosince cap. RNGTT adds an inverted guanosine group to the first transcribed nucleotide and RNMT methylates the guanosine cap at the N7-position.<br/>RNMT consists of a catalytic domain and an N-terminal domain that is absent in<br/>lower eukaryotes. Experiments presented in this thesis revealed that the N-terminus mediates RNMT recruitment to transcription start sites. Furthermore, it was found that the RNMT N-terminal domain is phosphorylated at Threonine-77 (T77) by CDK1/Cyclin B in a cell cycle-dependent manner during G2/M-phase.<br/>RNMT T77 phosphorylation activates cap methyltransferase activity in vitro. Furthermore, it negatively regulates the interaction of RNMT with KPNA2 (Importin-a), which was found to inhibit RNMT activity in vitro. RNMT T77 phosphorylation is required for normal cell proliferation suggesting an important biological function. Initial experiments indicated that RNMT T77 phosphorylation functions to regulate gene expression in a gene-specific manner. Future work is focused on establishing an experimental system to perform a genome-wide study in order to elucidate which transcripts are affected by RNMT T77 phosphorylation.<br/>To summarise, this study for the first time revealed that the RNA cap methyltransferase activity is regulated in a cell-cycle dependent manner.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

University of Dundee

Year dc:date.issued

2013

Author dc:creator

• Aregger, Michael

Advisor dc:contributor.advisor

• Cowling, Victoria

• RNMT
• Cap methylation
• Cap methyltransferase
• Phosphorylation
• Cell cycle
• Importin alpha
• KPNA2

Language dc:language

eng

Identifier

oai:discovery.dundee.ac.uk:studenttheses/3bf175e1-145e-4cbf-85d8-09affb50ac90

OAI identifier oai:identifier

oai:discovery.dundee.ac.uk:studenttheses/3bf175e1-145e-4cbf-85d8-09affb50ac90