Mark R Engle et al. (2002) Mid-west Worm Meeting "CeGSTP2-2, an invertebrate glutathione S-transferase with activity for 4-hydroxynonenal: possible roles in stress resistance and aging"

Piotr Zimniak, Robert Shmookler Reis, Mark R Engle, Eva Liebau, Srinivas Ayyadevara, Rajani Ayyadevara, Sharda Singh

[Mid-west Worm Meeting, 2002]

Reactive oxygen species (ROS) and oxidative stress are the inevitable consequence of aerobic metabolism. Enhancing organismal defenses that confer resistance to ROS, the primary initiators of the oxidative stress cascade, have been shown to play a pivotal role in extending the life span of invertebrates. In Drosophila, overexpression in motor neurons of superoxide dismutase-1 (SOD-1) can extend longevity by up to 40%. Similarly, characterization of the age-1 mutation in the nematode Caenorhabditis elegans demonstrated that the long-lived mutants have increased late life expression of catalase and SOD. These enzymes are thought to attenuate oxidative damage by lowering the level of initiating ROS. The mechanism by which ROS exerts damaging effects that ultimately lead to a shortened life span is not completely understood. The OH radicals can react with proteins and DNA directly, although more detrimental maybe their ability to initiate the lipid peroxidation cascade. This occurs when ROS react with poly-unsaturated fatty acids on the membrane in a self-propagating mechanism that can amplify the original insult 100-1000 fold. The resulting lipid hydroperoxides are oxidants themselves but they can decompose to form toxic electrophiles such as 4-hydroxynonenal (4HNE). 4HNE has a relatively long half-life, is diffusible, and can react with proteins and DNA leading to cellular dysfunction. Glutathione S-transferases are a multifunctional family of phase II detoxification enzymes that catalyze the conjugation of glutathione to toxins in order to make them more soluble and consequently less toxic. We have recently cloned and characterized a pi-class (P) C. elegans GST with a high level of activity for 4-HNE. Although this enzyme accounts for less than 20% of the total 4-HNE activity of worm homogenate, it appears to be highly expressed in the neurons (figure 1). It therefore may play a significant role in neuronal defense against toxic electrophiles. Because of the electrophilic protection afforded to this organism by the 4-HNE-conjugating activity of CeGSTP2-2, it is our hypothesis that nematodes with increased levels of CeGSTP2-2 may have increased resistance to stress and aging. Consistent with this hypothesis, we found that long-lived daf-2 mutants show increased expression of CeGSTP2-2.

Skourti-Stathaki K et al. (2013) Mol Cell "Histone 3 s10 phosphorylation: "caught in the R loop!"."

Skourti-Stathaki K, Proudfoot NJ

[Mol Cell, 2013]

In this issue of Molecular Cell, Castellano-Pozo etal. (2013) describe a connection between R loop structures and histone 3 S10 phosphorylation (H3S10P), a mark of chromatin compaction. Their results constitute asignificant advance in our understanding of the role of R loops in genomic instability.

Emerson F et al. (2020) Elife "A memory of longevity."

Lee SS, Li CL, Emerson F

[Elife, 2020]

Worms with increased levels of the epigenetic mark H3K9me2 have a longer lifespan that can be passed down to future generations.

Wu Y et al. (2017) Curr Top Dev Biol "Regulation of Cell Polarity by PAR-1/MARK Kinase."

Wu Y, Griffin EE

[Curr Top Dev Biol, 2017]

PAR-1/MARK kinases are conserved serine/threonine kinases that are essential regulators of cell polarity. PAR-1/MARK kinases localize and function in opposition to the anterior PAR proteins to control the asymmetric distribution of factors in a wide variety polarized cells. In this review, we discuss the mechanisms that control the localization and activity of PAR-1/MARK kinases, including their antagonistic interactions with the anterior PAR proteins. We focus on the role PAR-1 plays in the asymmetric division of the Caenorhabditis elegans zygote, in the establishment of the anterior/posterior axis in the Drosophila oocyte and in the control of microtubule dynamics in mammalian neurons. In addition to conserved aspects of PAR-1 biology, we highlight the unique ways in which PAR-1 acts in these distinct cell types to orchestrate their polarization. Finally, we review the connections between disruptions in PAR-1/MARK function and Alzheimer's disease and cancer.

Benecke M et al. (1994) Worm Breeder's Gazette "DNA Fingerprinting in C. elegans - An Approach."

Epplen JT, Schierenberg E, Benecke M

[Worm Breeder's Gazette, 1994]

DNA fingerprinting in C. elegans - an approach Mark Beneckea, Jorg T. Epplenb and Einhard Schierenberga a Zoologisches Institut der Univeritat, 50923 Koln, Germany b Ruhr-Universitat, Ab1. fur Molekulare Humangenetik, 44780 Bochum, Germany

Butkevich E et al. (2016) Sci Rep "Phosphorylation of FEZ1 by Microtubule Affinity Regulating Kinases regulates its function in presynaptic protein trafficking."

Grosche J, Erck C, Urlaub H, Nikolov M, Klopfenstein DR, Butkevich E, Chua JJ, Hartig W, Schmidt CF

[Sci Rep, 2016]

Adapters bind motor proteins to cargoes and therefore play essential roles in Kinesin-1 mediated intracellular transport. The regulatory mechanisms governing adapter functions and the spectrum of cargoes recognized by individual adapters remain poorly defined. Here, we show that cargoes transported by the Kinesin-1 adapter FEZ1 are enriched for presynaptic components and identify that specific phosphorylation of FEZ1 at its serine 58 regulatory site is mediated by microtubule affinity-regulating kinases (MARK/PAR-1). Loss of MARK/PAR-1 impairs axonal transport, with adapter and cargo abnormally co-aggregating in neuronal cell bodies and axons. Presynaptic specializations are markedly reduced and distorted in FEZ1 and MARK/PAR-1 mutants. Strikingly, abnormal co-aggregates of unphosphorylated FEZ1, Kinesin-1 and its putative cargoes are present in brains of transgenic mice modelling aspects of Alzheimer's disease, a neurodegenerative disorder exhibiting impaired axonal transport and altered MARK activity. Our findings suggest that perturbed FEZ1-mediated synaptic delivery of proteins arising from abnormal signalling potentially contributes to the process of neurodegeneration.

Castellano-Pozo M et al. (2013) Mol Cell "R loops are linked to histone H3 S10 phosphorylation and chromatin condensation."

Aguilera A, Castellano-Pozo M, Perez-Alegre M, Santos-Pereira JM, Barroso S, Garcia-Muse T, Andujar E, Rondon AG

[Mol Cell, 2013]

R loops are transcription byproducts that constitute athreat to genome integrity. Here we show that R loops are tightly linked to histone H3 S10 phosphorylation (H3S10P), a mark of chromatin condensation.Chromatin immunoprecipitation (ChIP)-on-chip (ChIP-chip) analyses reveal H3S10P accumulation at centromeres, pericentromeric chromatin, and a large number of active open reading frames (ORFs) in R-loop-accumulating yeast cells, better observed in G1. Histone H3S10 plays a key role in maintaining genome stability, as scored by ectopic recombination and plasmid loss, Rad52 foci, and Rad53 checkpoint activation. H3S10P coincides with the presence of DNA-RNA hybrids, is suppressed by ribonucleaseH overexpression, and causes reduced accessibility of restriction endonucleases, implying a tight connection between R loops, H3S10P, and chromatin compaction. Such histone modifications were also observed in R-loop-accumulating Caenorhabditis elegans and HeLa cells. We therefore provide a role of RNA in chromatin structure essential to understand how R loops modulate genome dynamics.

Bohdanowicz M et al. (2010) Curr Biol "Vesicular traffic: a Rab SANDwich."

Bohdanowicz M, Grinstein S

[Curr Biol, 2010]

The small GTPases Rab5 and Rab7 mark temporally distinct but sequentially connected stages in phagosome maturation, but the mechanism underlying the transition between these stages has been unclear. Recent studies in Caenorhabditis elegans have now uncovered a new protein complex that connects Rab5 to Rab7.

Hope IA (2001) Trends Genet "Broadcast interference - functional genomics."

Hope IA

[Trends Genet, 2001]

Four recent papers mark a major shift in functional genomic analysis for multicellular organisms. RNA-mediated interference was applied to inactivate individual genes systematically on a genomic scale. These studies subjected a third of the genes in the genome of Caenorhabditis elegans to reverse genetic analysis.

(1990) Worm Breeder's Gazette "CGC Bibliography in FileMaker and HyperCard (Mac) and Memory Mate ( IBM)"

[Worm Breeder's Gazette, 1990]

The CGC Bibliography has been translated into a couple of programs other than dBase by various worm people. David Barker and Andy Fire both have sent HyperCard versions to the CGC and Mark Blaxter has sent us a version in FileMaker 2.0. None of these is perfectly up-to-date, so you'll have to be somewhat familiar with the programs to add new references. The data files are available free from the CGC; to get yours, just send a blank 3.5' diskette to Mark Edgley at the CGC with a request letter. In addition, Lew Jacobson has translated the bibliography into a DOS program called Memory Mate and he is willing to distribute the data file to anyone who sends him a blank 5.25' 360 Kb diskette. Memory Mate can be operated as a TSR and called up with a hotkey from the middle of a word processor or other program. Addresses for Mark and Lew can be found in the Subscriber Directory Update in this issue.