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Gary Ruvkun

Nicolas J Lehrbach, Gary Ruvkun
Proteasomes are essential for protein homeostasis in eukaryotes. To preserve cellular function, transcription of proteasome subunit genes is induced in response to proteasome dysfunction caused by pathogen attacks or proteasome inhibitor drugs. In Caenorhabditis elegans, this response requires SKN-1, a transcription factor related to mammalian Nrf1/2. Here, we use comprehensive genetic analyses to identify the pathway required for C. elegans to detect proteasome dysfunction and activate SKN-1. Genes required for SKN-1 activation encode regulators of ER traffic, a peptide N-glycanase, and DDI-1, a conserved aspartic protease...
2016: ELife
Robert H Dowen, Peter C Breen, Thomas Tullius, Annie L Conery, Gary Ruvkun
Animals integrate metabolic, developmental, and environmental information before committing key resources to reproduction. In Caenorhabditis elegans, adult animals transport fat from intestinal cells to the germline to promote reproduction. We identified a microRNA (miRNA)-regulated developmental timing pathway that functions in the hypodermis to nonautonomously coordinate the mobilization of intestinal fat stores to the germline upon initiation of adulthood. This developmental timing pathway, which is controlled by the lin-4 and let-7 miRNAs, engages mTOR signaling in the intestine...
July 1, 2016: Genes & Development
Buck S Samuel, Holli Rowedder, Christian Braendle, Marie-Anne Félix, Gary Ruvkun
Most Caenorhabditis elegans studies have used laboratory Escherichia coli as diet and microbial environment. Here we characterize bacteria of C. elegans' natural habitats of rotting fruits and vegetation to provide greater context for its physiological responses. By the use of 16S ribosomal DNA (rDNA)-based sequencing, we identified a large variety of bacteria in C. elegans habitats, with phyla Proteobacteria, Bacteroidetes, Firmicutes, and Actinobacteria being most abundant. From laboratory assays using isolated natural bacteria, C...
July 5, 2016: Proceedings of the National Academy of Sciences of the United States of America
Petra Rettberg, Alexandre M Anesio, Victor R Baker, John A Baross, Sherry L Cady, Emmanouil Detsis, Christine M Foreman, Ernst Hauber, Gian Gabriele Ori, David A Pearce, Nilton O Renno, Gary Ruvkun, Birgit Sattler, Mark P Saunders, David H Smith, Dirk Wagner, Frances Westall
We highlight the role of COSPAR and the scientific community in defining and updating the framework of planetary protection. Specifically, we focus on Mars "Special Regions," areas where strict planetary protection measures have to be applied before a spacecraft can explore them, given the existence of environmental conditions that may be conducive to terrestrial microbial growth. We outline the history of the concept of Special Regions and inform on recent developments regarding the COSPAR policy, namely, the MEPAG SR-SAG2 review and the Academies and ESF joint committee report on Mars Special Regions...
February 2016: Astrobiology
J Amaranath Govindan, Elamparithi Jayamani, Xinrui Zhang, Eleftherios Mylonakis, Gary Ruvkun
The microbial world presents a complex palette of opportunities and dangers to animals, which have developed surveillance and response strategies to hints of microbial intent. We show here that the mitochondrial homeostatic response pathway of the nematode Caenorhabditis elegans responds to Escherichia coli mutations that activate free radical detoxification pathways. Activation of C. elegans mitochondrial responses could be suppressed by additional mutations in E. coli, suggesting that C. elegans responds to products of E...
October 6, 2015: Proceedings of the National Academy of Sciences of the United States of America
J Amaranath Govindan, Elamparithi Jayamani, Xinrui Zhang, Peter Breen, Jonah Larkins-Ford, Eleftherios Mylonakis, Gary Ruvkun
Translation in eukaryotes is followed to detect toxins and virulence factors and coupled to the induction of defence pathways. Caenorhabditis elegans germline-specific mutations in translation components are detected by this system to induce detoxification and immune responses in distinct somatic cells. An RNA interference screen revealed gene inactivations that act at multiple steps in lipid biosynthetic and kinase pathways upstream of MAP kinase to mediate the systemic communication of translation defects to induce detoxification genes...
October 2015: Nature Cell Biology
Carolyn M Phillips, Kristen C Brown, Brooke E Montgomery, Gary Ruvkun, Taiowa A Montgomery
piRNAs silence foreign genes, such as transposons, to preserve genome integrity, but they also target endogenous mRNAs by mechanisms that are poorly understood. Caenorhabditis elegans piRNAs interact with both transposon and nontransposon mRNAs to initiate sustained silencing via the RNAi pathway. To assess the dysregulation of gene silencing caused by lack of piRNAs, we restored RNA silencing in RNAi-defective animals in the presence or absence of piRNAs. In the absence of piRNAs and a cellular memory of piRNA activity, essential and conserved genes are misrouted into the RNAi pathway to produce siRNAs that bind the nuclear Argonaute HRDE-1, resulting in dramatic defects in germ cell proliferation and function such that the animals are sterile...
August 24, 2015: Developmental Cell
Ilyas R Sadreyev, Fei Ji, Emiliano Cohen, Gary Ruvkun, Yuval Tabach
Proteins that function in the same pathways, protein complexes or the same environmental conditions can show similar patterns of sequence conservation across phylogenetic clades. In species that no longer require a specific protein complex or pathway, these proteins, as a group, tend to be lost or diverge. Analysis of the similarity in patterns of sequence conservation across a large set of eukaryotes can predict functional associations between different proteins, identify new pathway members and reveal the function of previously uncharacterized proteins...
July 1, 2015: Nucleic Acids Research
Natalia V Kirienko, Frederick M Ausubel, Gary Ruvkun
In the arms race of bacterial pathogenesis, bacteria produce an array of toxins and virulence factors that disrupt core host processes. Hosts mitigate the ensuing damage by responding with immune countermeasures. The iron-binding siderophore pyoverdin is a key virulence mediator of the human pathogen Pseudomonas aeruginosa, but its pathogenic mechanism has not been established. Here we demonstrate that pyoverdin enters Caenorhabditis elegans and that it is sufficient to mediate host killing. Moreover, we show that iron chelation disrupts mitochondrial homeostasis and triggers mitophagy both in C...
February 10, 2015: Proceedings of the National Academy of Sciences of the United States of America
J Amaranath Govindan, Gary Ruvkun
No abstract text is available yet for this article.
2014: Virulence
Meng C Wang, Holly D Oakley, Christopher E Carr, Jessica N Sowa, Gary Ruvkun
Reproductive senescence is a hallmark of aging. The molecular mechanisms regulating reproductive senescence and its association with the aging of somatic cells remain poorly understood. From a full genome RNA interference (RNAi) screen, we identified 32 Caenorhabditis elegans gene inactivations that delay reproductive senescence and extend reproductive lifespan. We found that many of these gene inactivations interact with insulin/IGF-1 and/or TGF-β endocrine signaling pathways to regulate reproductive senescence, except nhx-2 and sgk-1 that modulate sodium reabsorption...
December 2014: PLoS Genetics
J Amaranath Govindan, Gary Ruvkun
No abstract text is available yet for this article.
October 7, 2014: Virulence
Susana M D A Garcia, Yuval Tabach, Guinevere F Lourenço, Maria Armakola, Gary Ruvkun
Myotonic dystrophy disorders are caused by expanded CUG repeats in noncoding regions. Here we used Caenorhabditis elegans expressing CUG repeats to identify genes that modulate the toxicity of such repeats. We identified 15 conserved genes that function as suppressors or enhancers of CUG repeat-induced toxicity and that modulate formation of nuclear foci by CUG-repeat RNA. These genes regulate CUG repeat-induced toxicity through distinct mechanisms including RNA export and clearance, thus suggesting that CUG-repeat toxicity is mediated by multiple pathways...
August 2014: Nature Structural & Molecular Biology
Ying Liu, Buck S Samuel, Peter C Breen, Gary Ruvkun
Mitochondrial function is challenged by toxic by-products of metabolism as well as by pathogen attack. Caenorhabditis elegans normally responds to mitochondrial dysfunction with activation of mitochondrial-repair, drug-detoxification and pathogen-response pathways. Here, from a genome-wide RNA interference (RNAi) screen, we identified 45 C. elegans genes that are required to upregulate detoxification, pathogen-response and mitochondrial-repair pathways after inhibition of mitochondrial function by drug-induced or genetic disruption...
April 17, 2014: Nature
Carolyn M Phillips, Brooke E Montgomery, Peter C Breen, Elke F Roovers, Young-Soo Rim, Toshiro K Ohsumi, Martin A Newman, Josien C van Wolfswinkel, Rene F Ketting, Gary Ruvkun, Taiowa A Montgomery
More than 2,000 C. elegans genes are targeted for RNA silencing by the mutator complex, a specialized small interfering RNA (siRNA) amplification module which is nucleated by the Q/N-rich protein MUT-16. The mutator complex localizes to Mutator foci adjacent to P granules at the nuclear periphery in germ cells. Here, we show that the DEAD box RNA helicase smut-1 functions redundantly in the mutator pathway with its paralog mut-14 during RNAi. Mutations in both smut-1 and mut-14 also cause widespread loss of endogenous siRNAs...
April 14, 2014: Current Biology: CB
Sylvia E J Fischer, Qi Pan, Peter C Breen, Yan Qi, Zhen Shi, Chi Zhang, Gary Ruvkun
Gene segments from other organisms, such as viruses, are detected as foreign and targeted for silencing by RNAi pathways. A deep-sequencing map of the small RNA response to repeated transgenes introduced to Caenorhabditis elegans revealed that specific segments are targeted by siRNAs. Silencing of the foreign gene segments depends on an antiviral response that involves changes in active and silent chromatin modifications and altered levels of antisense siRNAs. Distinct Argonaute proteins target foreign genes for silencing or protection against silencing...
December 15, 2013: Genes & Development
Schraga Schwartz, Sudeep D Agarwala, Maxwell R Mumbach, Marko Jovanovic, Philipp Mertins, Alexander Shishkin, Yuval Tabach, Tarjei S Mikkelsen, Rahul Satija, Gary Ruvkun, Steven A Carr, Eric S Lander, Gerald R Fink, Aviv Regev
N(6)-methyladenosine (m(6)A) is the most ubiquitous mRNA base modification, but little is known about its precise location, temporal dynamics, and regulation. Here, we generated genomic maps of m(6)A sites in meiotic yeast transcripts at nearly single-nucleotide resolution, identifying 1,308 putatively methylated sites within 1,183 transcripts. We validated eight out of eight methylation sites in different genes with direct genetic analysis, demonstrated that methylated sites are significantly conserved in a related species, and built a model that predicts methylated sites directly from sequence...
December 5, 2013: Cell
Alexander A Soukas, Christopher E Carr, Gary Ruvkun
Lysosomes are membrane-bound organelles that contain acid hydrolases that degrade cellular proteins, lipids, nucleic acids, and oligosaccharides, and are important for cellular maintenance and protection against age-related decline. Lysosome related organelles (LROs) are specialized lysosomes found in organisms from humans to worms, and share many of the features of classic lysosomes. Defective LROs are associated with human immune disorders and neurological disease. Caenorhabditis elegans LROs are the site of concentration of vital dyes such as Nile red as well as age-associated autofluorescence...
October 2013: PLoS Genetics
Yuval Tabach, Tamar Golan, Abrahan Hernández-Hernández, Arielle R Messer, Tomoyuki Fukuda, Anna Kouznetsova, Jian-Guo Liu, Ingrid Lilienthal, Carmit Levy, Gary Ruvkun
Genes with common profiles of the presence and absence in disparate genomes tend to function in the same pathway. By mapping all human genes into about 1000 clusters of genes with similar patterns of conservation across eukaryotic phylogeny, we determined that sets of genes associated with particular diseases have similar phylogenetic profiles. By focusing on those human phylogenetic gene clusters that significantly overlap some of the thousands of human gene sets defined by their coexpression or annotation to pathways or other molecular attributes, we reveal the evolutionary map that connects molecular pathways and human diseases...
2013: Molecular Systems Biology
Zhen Shi, Gabriel Hayes, Gary Ruvkun
microRNAs (miRNAs) are ∼22 nt regulatory RNAs that in animals typically bind with partial complementarity to sequences in the 3' untranslated (UTR) regions of target mRNAs, to induce a decrease in the production of the encoded protein. The relative contributions of translational inhibition of intact mRNAs and degradation of mRNAs caused by binding of the miRNA vary; for many genetically validated miRNA targets, translational repression has been implicated, whereas some analyses of other miRNA targets have revealed only modest translational repression and more significant mRNA destabilization...
2013: PloS One
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