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Identifier 000383933
Title The role of mRNA turnover in ageing of Caenorhabditis elegans : novel tools for microscopic 3D imaging
Alternative Title Ο ρόλος της αποδόμησης του mRNA στη γήρανση του Caenorhabditis elegans.
Author Rieckher, Matthias
Thesis advisor Δελιδάκης, Χρήστος
Reviewer Ταβερναράκης, Νεκτάριος
Ηλιόπουλος, Αριστείδης
Abstract Alterations of general or specific mRNA levels are a universal manifestation of the ageing process (Cookson, 2011). During their existence, mRNAs are constantly decorated by dynamically changing factors, which form messenger ribonucleoprotein (mRNP) complexes and determine the fate of an mRNA. Mechanisms that control mRNA turnover in the cytoplasm have been described in great detail but whether they might be involved in the regulation of ageing is unknown (Anderson and Kedersha, 2009; Decker and Parker, 2012). Bulk mRNA decay in eukaryotes is initiated by irreversible shortening of the poly(A)-tail, subsequent decapping and final 5’ to 3’ degradation (Houseley and Tollervey, 2009). We present compelling evidence that EDC-3, a highly conserved modulator of decapping, is a novel determinant of ageing in C. elegans. Decapping has been shown to regulate protein synthesis by competing with the mechanism of translation initiation. Congruently, we find that EDC-3 regulates protein synthesis and lifespan in interaction with the previously described translation initiation factor IFE-2, an isoform of the human eIF4E, which has a conserved role in the control of ageing. We demonstrate that EDC-3 and IFE-2 mediated regulation of C. elegans lifespan happens specifically in neuronal tissue and governs neural integrity. Further, we show that loss of EDC-3 protects from oxidative and heat induced stress and that lifespan extension depends on the activity of Nrf-like xenobiotic- response factor SKN-1 and heat shock response factor HSF-1. Also, longevity upon loss of EDC-3 triggers a ROS induced hormesis response that depends on SKN-1 activity. Most mRNPs accumulate in distinct cellular foci termed processing bodies (P-bodies) or stress granules, which store mRNAs stalled in modes of degradation or translation initiation (Sheth and Parker, 2003, reviewed in Decker and Parker, 2012; Franks and Lykke-Andersen, 2008). Decapping factors, including EDC-3, are part of P-bodies, while IFE-2 localizes to stress granules in C. elegans. We establish an increased formation of P-bodies and stress granules and their co-localization upon specific stress insults and during age in the nematode, thereby defining them as biomarkers of ageing. It is unknown, whether mRNP granule formation is cause or consequence of mRNA decay and stress response (Eulalio et al., 2007). We demonstrate, that loss of SKN-1 contributes to an increased formation of P-bodies upon oxidative stress. Curiously, down-regulation of HSF-1 prevents P-body assembly specifically upon heat stress and causes age-related granulation of IFE-2. These results implicate that mRNP aggregation is a transcriptionally controlled process that contributes to maintenance of cellular stress response and ageing. Unexpectedly, we find that HSF-1 suppresses transcription, stability and nuclear granulation of IFE-2 during ageing. These granules co-localize with components of P-bodies at the nuclear envelope, which also have been shown to be involved in transcription regulation in the nucleus (summarized in Reines, 2012). Excitingly, we observe decreased localization of IFE- 2 in the nucleus, upon depletion of EDC-3. Our findings suggest that HSF-1 modulates IFE-2 function and localization during ageing, and that IFE-2 also serves as nuclear mRNP export factor in C. elegans. Thus, IFE-2 likely mediates the effects of the heat stress response on both mRNA translation and degradation to influence ageing.
Language English
Subject C.elegans
EDC-3
P-bodies
Stress granules
Σωμάτια επεξεργασίας
Issue date 2013-07-11
Collection   School/Department--School of Sciences and Engineering--Department of Biology--Doctoral theses
  Type of Work--Doctoral theses
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