The role of the RNA 5' end cap in the regulation of gene expression

Zanin, Onofrio (2023). The role of the RNA 5' end cap in the regulation of gene expression. University of Birmingham. Ph.D.

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Abstract

The 5’ RNA capping is an essential process conserved in the entire eukaryotic kingdom. It consists in the co-transcriptional addition of a 7-methylguanosine (m\(^7\)G) residue to the 5’ end of the products of the RNA polymerase II. The m\(^7\)G cap mediates several processes such as the RNA maturation and nuclear export as well as the mRNA translation. The main function of the m\(^7\)G cap is thought to be limited to the protection of the RNA from the exonucleolytic degradation and to the interaction with cap binding proteins (CBPs) directly involved in many RNA processing pathways.

The work presented here aims to provide a global description of the role of the m\(^7\)G cap by investigating the events affecting the expression of cap defective RNAs in the yeast Saccharomyces cerevisiae (S. cerevisiae). The introduction of capping defects via the fast depletion of the capping enzymes, revealed complex dynamics related to the readjustments in the levels of non-capped mRNAs which resulted determined by their basal expression levels. The cap deficiency induced the preferential degradation of highly expressed RNAs along with the accumulation of lowly expressed transcripts. The effect was recapitulated upon the disruption of the 5’-3’ exonuclease Xrn1 suggesting a correlation between the two events. Finally, contradicting the cap quality control paradigm, the transcription of uncapped pre-mRNAs is not prematurely terminated in capping enzymes depleted cells.

The evidence reported indicate a critical role of the m\(^7\)G cap in the Xrn1-mediated sensing and regulation of the cellular mRNA levels expanding the complexity in the function of this RNA modification and introducing a further layer of control in the regulation of gene expression.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):