Ryan Langley

Up-frameshift protein 1 (Upf1) is a multidomain RNA helicase that is conserved from yeast to humans. Upf1 is critical for nonsense-mediated decay (NMD), a quality control mechanism that detects and eliminates aberrant transcripts harbouring a premature termination codon (PTC) and thus plays an important role in maintaining the fidelity of gene expression. Additionally, Upf1 is implicated in a broad range of cellular responses from chromosome maintenance to mRNA degradation and translational repression. Recent findings show that Upf1 also triggers 3′ end mRNA tagging, the addition of non-templated pyrimidines (C/U) to the 3′ end of adenylated and non-adenylated (histone) mRNAs. 3′ end tagging is seen as a general precursor of mRNA degradation and has been found to occur in fungi, plants and mammals. In Aspergillus nidulans, 3′ end tagging of normal and aberrant transcripts containing PTCs occurs in an Upf1-dependent manner. Intriguingly, tagging of transcripts harbouring PTCs is not essential for transcript degradation as the disruption of either of the two enzymes that mediate 3′ end RNA tagging, CutA and CutB results in decreased efficiency of ribosome dissociation from the PTC. However, the exact role of Upf1 and its functional domains in inducing tagging and ribosome dissociation remains unknown. Therefore, the aim of this work is to propose a model for the detailed mutational analysis of A. nidulans Upf1 in relation to its role in triggering 3′ end tagging and translation termination. From published data of mutation analysis, active site residues of the yeast and human Upf1 proteins have been identified and aligned to their A. nidulans homologue. Analysis of the structural organization of A. nidulans Upf1 reveals the presence of two major conserved domains and a number of putative actives site residues which may be crucial for 3′ end mRNA tagging, translational repression and ribosome termination. The importance of a greater understanding of the role of Upf1 in regulation of gene expression in A. nidulans, a model organism for Aspergillus species of medical and industrial importance, is discussed.