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The role of Elongator complex in Saccharomyces cerevisiae and Caenorhabditis elegans
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). (Anders Byström)
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
Umeå: Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet), Umeå Universitet , 2011. , 38 p.
Identifiers
URN: urn:nbn:se:umu:diva-43348ISBN: 978-91-7459-176-7OAI: oai:DiVA.org:umu-43348DiVA: diva2:413119
Public defence
2011-05-20, Byggnad 6 L, Major Groove, Umeå universitet, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2011-04-29 Created: 2011-04-27 Last updated: 2011-04-28Bibliographically approved
List of papers
1. Elongator complex influences the transcriptional silencing and DNA damage response by its role in wobble uridine tRNA modification
Open this publication in new window or tab >>Elongator complex influences the transcriptional silencing and DNA damage response by its role in wobble uridine tRNA modification
(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:umu:diva-43332 (URN)
Available from: 2011-04-27 Created: 2011-04-27 Last updated: 2011-04-28
2. Elongator complex enhances Rnr1 induction in response to DNA damage by promoting Ixr1 expression
Open this publication in new window or tab >>Elongator complex enhances Rnr1 induction in response to DNA damage by promoting Ixr1 expression
(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:umu:diva-43333 (URN)
Available from: 2011-04-27 Created: 2011-04-27 Last updated: 2011-04-28
3. Defects in tRNA modification associated with neurological and developmental dysfunctions in Caenorhabditis elegans elongator mutants
Open this publication in new window or tab >>Defects in tRNA modification associated with neurological and developmental dysfunctions in Caenorhabditis elegans elongator mutants
2009 (English)In: PLoS genetics, ISSN 1553-7404, Vol. 5, no 7, e1000561- p.Article in journal (Refereed) Published
Abstract [en]

Elongator is a six subunit protein complex, conserved from yeast to humans. Mutations in the human Elongator homologue, hELP1, are associated with the neurological disease familial dysautonomia. However, how Elongator functions in metazoans, and how the human mutations affect neural functions is incompletely understood. Here we show that in Caenorhabditis elegans, ELPC-1 and ELPC-3, components of the Elongator complex, are required for the formation of the 5-carbamoylmethyl and 5-methylcarboxymethyl side chains of wobble uridines in tRNA. The lack of these modifications leads to defects in translation in C. elegans. ELPC-1::GFP and ELPC-3::GFP reporters are strongly expressed in a subset of chemosensory neurons required for salt chemotaxis learning. elpc-1 or elpc-3 gene inactivation causes a defect in this process, associated with a posttranscriptional reduction of neuropeptide and a decreased accumulation of acetylcholine in the synaptic cleft. elpc-1 and elpc-3 mutations are synthetic lethal together with those in tuc-1, which is required for thiolation of tRNAs having the 5'methylcarboxymethyl side chain. elpc-1; tuc-1 and elpc-3; tuc-1 double mutants display developmental defects. Our results suggest that, by its effect on tRNA modification, Elongator promotes both neural function and development.

Identifiers
urn:nbn:se:umu:diva-32160 (URN)10.1371/journal.pgen.1000561 (DOI)19593383 (PubMedID)
Available from: 2010-03-03 Created: 2010-03-03 Last updated: 2011-04-28Bibliographically approved
4. Allele-specific suppressors of lin-1(R175Opal) identify functions of MOC-3 and DPH-3 in tRNA modification complexes in Caenorhabditis elegans
Open this publication in new window or tab >>Allele-specific suppressors of lin-1(R175Opal) identify functions of MOC-3 and DPH-3 in tRNA modification complexes in Caenorhabditis elegans
Show others...
2010 (English)In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 185, no 4, 1235-1247 p.Article in journal (Refereed) Published
Abstract [en]

The elongator (ELP) complex consisting of Elp1-6p has been indicated to play roles in multiple cellular processes. In yeast, the ELP complex has been shown to genetically interact with Uba4p/Urm1p and Kti11-13p for a function in tRNA modification. Through a Caenorhabditis elegans genetic suppressor screen and positional cloning, we discovered that loss-of-function mutations of moc-3 and dph-3, orthologs of the yeast UBA4 and KTI11, respectively, effectively suppress the Multivulva (Muv) phenotype of the lin-1(e1275, R175Opal) mutation. These mutations do not suppress the Muv phenotype caused by other lin-1 alleles or by gain-of-function alleles of ras or raf that act upstream of lin-1. The suppression can also be reverted by RNA interference of lin-1. Furthermore, we showed that dph-3(lf) also suppressed the defect of lin-1(e1275) in promoting the expression of a downstream target (egl-17). These results indicate that suppression by the moc-3 and dph-3 mutations is due to the elevated activity of lin-1(e1275) itself rather than the altered activity of a factor downstream of lin-1. We further showed that loss-of-function mutations of urm-1 and elpc-1-4, the worm counterparts of URM1 and ELP complex components in yeast, also suppressed lin-1(e1275). We also confirmed that moc-3(lf) and dph-3(lf) have defects in tRNA modifications as do the mutants of their yeast orthologs. These results, together with the observation of a likely readthrough product from a lin-1(e1275)∷gfp fusion transgene indicate that the aberrant tRNA modification led to failed recognition of a premature stop codon in lin-1(e1275). Our genetic data suggest that the functional interaction of moc-3/urm-1 and dph-3 with the ELP complex is an evolutionarily conserved mechanism involved in tRNA functions that are important for accurate translation.

Place, publisher, year, edition, pages
Genetics Society of America, 2010
Keyword
adp-ribosylating toxins, saccharomyces-cerevisiae, c-elegans, elongator complex, cell fates, vulval induction, transcriptional elongation, modifier urm1, ets-domain, protein
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-43347 (URN)10.1534/genetics.110.118406 (DOI)000281907700009 ()
Available from: 2011-04-27 Created: 2011-04-27 Last updated: 2011-10-06Bibliographically approved

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