Functional characterisation of pncr003;2L, a small open reading frame gene conserved from drosophila to humans

Magny, Emile Gerard (2014) Functional characterisation of pncr003;2L, a small open reading frame gene conserved from drosophila to humans. Doctoral thesis (PhD), University of Sussex.

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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 calciumtrafficking 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

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics > QH0470.A-Z Experimental organisms, A-Z > QH0470.D7 Drosophila
Depositing User: Library Cataloguing
Date Deposited: 17 Jun 2014 09:09
Last Modified: 21 Sep 2015 15:00
URI: http://sro.sussex.ac.uk/id/eprint/48976

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