Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.606094
Title: Functional characterisation of pncr003;2L, a small open reading frame gene conserved from Drosophila to humans
Author: Magny, Emile Gerard
ISNI:       0000 0004 5360 8255
Awarding Body: University of Sussex
Current Institution: University of Sussex
Date of Award: 2014
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Abstract:
Small open reading frame genes (smORFs) are a new class of genes, which emerged from the revision of the idea that open reading frames have to be longer than 100 codons to be protein coding and functional. Although bio-informatics evidence suggests that thousands of smORF genes could exist in any given genome, proof of their functional relevance can only be obtained through their functional characterization. This work represents such a study for a Drosophila smORF (pncr003;2L), which was initially misannotated as a non-coding RNA because of its lack of a canonical long open reading frame. Here I show that pncr003;2L codes for two small peptides of 28 and 29 aa, expressed in somatic and cardiac muscles. After generating a null condition for this gene, I use the adult Drosophila heart as a system to assess the function of pncr003;2L. With this system, I show that the small pncr003;2L peptides regulate heart contractions by modulating Ca2+ cycling in cardiac muscles, with either lack or excess of function of these peptides leading to cardiac arrhythmias, and abnormal calcium dynamics. Finally, through an extensive homology study, I show that these small peptides share a great amount of structural and functional homology with the peptides encoded by the vertebrate smORFs sarcolipin (sln) and phospoholamban (pln), which act as major regulators of the Sarco-Endoplasmic Reticulum Calcium ATPase (SERCA), the channel responsible for calcium uptake into the ER following muscle contraction. These results highlight the importance of the pncr003;2L smORF and the Drosophila system, for the study of cardiac pathologies, but most importantly, they show that this family of peptides, conserved across evolution, represent an ancient system for the regulation of calcium trafficking in muscles. This work corroborates the prevalence, and relevance of this novel class of genes, and shows that closer attention should be given to smORFs in order to determine the full extent of their biological contribution.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.606094  DOI: Not available
Keywords: QH0470.D7 Drosophila
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