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[
Epigenomics,
2022]
In this interview, Professor Susan Gasser speaks with Storm Johnson, commissioning editor for <i>Epigenomics</i>, on her research on genome stability, epigenetic regulation and chromatin organization, as well as her work supporting women in research. Susan Gasser completed her BA at the University of Chicago, with an honors thesis in biophysics, and her PhD in biochemistry at the University of Basel in 1982, with Gottfried Schatz. She was a postdoc with Ulrich Laemmli at the University of Geneva, which initiated her career-long interest in chromosomes and chromatin structure. She established her own laboratory at the Swiss Institute for Experimental Cancer Research (ISREC) in 1986, focusing on chromatin organization in budding yeast, combining genetics, microscopy and biochemical approaches to understanding silent chromatin and telomeres. In 2001, she was named professor of molecular biology at the University of Geneva and expanded her laboratory's pioneering use of high-resolution time-lapse fluorescence microscopy to study single locus dynamics in the nucleus. From 2004 to 2019, Susan was the Director of the Friedrich Miescher Institute for Biomedical Research in Basel, where she also led a research group until the end of 2020. In Basel, she extended her research interests into heterochromatin in <i>Caenorhabditiselegans</i>. Her laboratory identified the mechanisms that position tissue-specific genesin the nuclei ofembryos and ofdifferentiated tissues, combining high throughput molecular analyses with cell biology to determine structure-function relationships in chromatin. Since January 2021, Susan Gasser has been <i>professor invite</i> at the University of Lausanne and Director of the ISREC Foundation, where she is helping shape the new Agora Institute of Translational Cancer Research. She was elected to the Academie de France, Leopoldina, European Molecular Biology Organization (EMBO), American Association for the Advancement of Science and Swiss Academy of Medical Sciences, and she received the French National Institute of Health and Medical Research (INSERM) International Prize in 2011, the Federation of European Biochemical Societies | EMBO Women in Science Award in 2012, the Weizmann Institute Women in Science Award in 2013 and honorary doctorates from the University of Lausanne, the University of Fribourg and Charles University in Prague. In Switzerland, she was the recipient of the Friedrich Miescher Award, the National Latsis Prize and the Otto Naegeli Award for the promotion of medical research. She participates in numerous review boards and advisory committees in Switzerland, across Europe and in Japan; she currently serves on the governing board of the Swiss Federal Institutes of Technology and the Swiss Science Council. From 2000 to 2004, she was vice chairperson, then chairperson of the EMBO Council. Susan led the Gender Committee of the Swiss National Science Foundation from 2014 to 2019 and initiated the Swiss National Science FoundationPrima program for the Promotion of women in academia. She has actively promotedthe careers of women scientists in Europe and Japan.
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[
Development,
2018]
Susan Strome is Distinguished Professor of Molecular, Cell and Developmental Biology at the University of California, Santa Cruz, USA. Recently appointed an editor at Development, her lab studies the regulation of germ cell development in<i>C. elegans</i>, with a particular focus on the epigenetic transmission of chromatin states. We caught up with Susan to discuss her early career switch from prokaryotes to worms, her experiences of small and big science, and why teaching is so important to her.
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[
Mol Biol Cell,
2005]
Monitoring Editor: Susan Strome The defecation behavior of the nematode Caenorhabditis elegans is controlled by a 45-s ultradian rhythm. An essential component of the clock that regulates the rhythm is the inositol trisphosphate receptor in the intestine, but other components remain to be discovered. Here, we show that the
flr-4 gene, whose mutants exhibit very short defecation cycle periods, encodes a novel serine/threonine protein kinase with a carboxyl terminal hydrophobic region. The expression of functional
flr-4::GFP was detected in the intestine, part of pharyngeal muscles and a pair of neurons, but expression of
flr-4 in the intestine was sufficient for the wild-type phenotype. Furthermore, laser killing of the
flr-4-expressing neurons did not change the defecation phenotypes of wild-type and
flr-4 mutant animals. Temperature-shift experiments with a temperature-sensitive
flr-4 mutant suggested that FLR-4 acts in a cell-functional rather than developmental aspect in the regulation of defecation rhythms. The function of FLR-4 was impaired by missense mutations in the kinase domain and near the hydrophobic region, where the latter allele seemed to be a weak antimorph. Thus, a novel protein kinase with a unique structural feature acts in the intestine to increase the length of defecation cycle periods.
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Sternberg PW, Ansell BRE, Andrews KT, Nowell C, Chang BCH, Hofmann A, Crawford S, Korhonen PK, Baell J, Gijs MAM, Fisher GM, Young ND, Preston S, Mouchiroud L, Gasser RB, Jabbar A, Auwerx J, Davis RA, McGee SL, Cornaglia M
[
FASEB J,
2017]
As a result of limited classes of anthelmintics and an over-reliance on chemical control, there is a great need to discover new compounds to combat drug resistance in parasitic nematodes. Here, we show that deguelin, a plant-derived rotenoid, selectively and potently inhibits the motility and development of nematodes, which supports its potential as a lead candidate for drug development. Furthermore, we demonstrate that deguelin treatment significantly increases gene transcription that is associated with energy metabolism, particularly oxidative phosphorylation and mito-ribosomal protein production before inhibiting motility. Mitochondrial tracking confirmed enhanced oxidative phosphorylation. In accordance, real-time measurements of oxidative phosphorylation in response to deguelin treatment demonstrated an immediate decrease in oxygen consumption in both parasitic (Haemonchus contortus) and free-living (Caenorhabditis elegans) nematodes. Consequently, we hypothesize that deguelin is exerting its toxic effect on nematodes as a modulator of oxidative phosphorylation. This study highlights the dynamic biologic response of multicellular organisms to deguelin perturbation.-Preston, S., Korhonen, P. K., Mouchiroud, L., Cornaglia, M., McGee, S. L., Young, N. D., Davis, R. A., Crawford, S., Nowell, C., Ansell, B. R. E., Fisher, G. M., Andrews, K. T., Chang, B. C. H., Gijs, M. A. M., Sternberg, P. W., Auwerx, J., Baell, J., Hofmann, A., Jabbar, A., Gasser, R. B. Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain.
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[
Mol Biol Cell,
2005]
Monitoring Editor: Susan Strome Investigation of Caenorhabditis elegans
act-5 gene function revealed that intestinal microvillus formation requires a specific actin isoform. ACT-5 is the most diverged of the five C. elegans actins, sharing only 93% identity with the other four. GFP reporter and immunofluoresence analysis indicated that
act-5 gene expression is limited to microvillus -containing cells within the intestine and excretory systems, and that ACT-5 is apically localized within intestinal cells. Animals heterozygous for a dominant
act-5 mutation appeared clear and thin, and grew slowly. Animals homozygous for either the dominant
act-5 mutation, or a recessive loss of function mutant, exhibited normal morphology and intestinal cell polarity, but died during the first larval stage. Ultrastructural analysis revealed a complete loss of intestinal microvilli in homozygous
act-5 mutants. Forced expression of ACT-1 under the control of the
act-5 promoter did not rescue the lethality of the
act-5 mutant. Taken together with immuno-EM experiments that indicated ACT-5 is enriched within microvilli themselves, these results suggest a microvillus - specific function for
act-5 and, further, raise the possibility that specific actins may be specialized for building microvilli and related structures.
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[
Mol Biol Cell,
2005]
Monitoring Editor: Susan Strome During mitosis, chromosome segregation is regulated by a spindle checkpoint mechanism. This checkpoint delays anaphase until all kinetochores are captured by microtubules from both spindle poles, chromosomes congress to the metaphase plate, and the tension between kinetochores and their attached microtubules is properly sensed. While the spindle checkpoint can be activated in many different cell types, the role of this regulatory mechanism in rapidly dividing embryonic animal cells has remained controversial. Here, using time-lapse imaging of live embryonic cells, we show that chemical or mutational disruption of the mitotic spindle in early C. elegans embryos delays progression through mitosis. By reducing the function of conserved checkpoint genes in mutant embryos with defective mitotic spindles, we show that these delays require the spindle checkpoint. We also show that the conserved kinesin CeMCAK, the CENP-F-related proteins HCP-1 and HCP-2, and the core kinetochore protein CeCENP-C all are required for this checkpoint. In the absence of a functional checkpoint, more severe defects in chromosome segregation are observed in mutants with abnormal mitotic spindles. Our analysis indicates that spindle checkpoint mechanisms are functional in the rapidly dividing cells of an early animal embryo, and that this checkpoint can prevent chromosome segregation defects during mitosis.
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[
FASEB J,
2016]
The trehalose biosynthetic pathway is of great interest for the development of novel therapeutics because trehalose is an essential disaccharide in many pathogens but is neither required nor synthesized in mammalian hosts. As such, trehalose-6-phosphate phosphatase (TPP), a key enzyme in trehalose biosynthesis, is likely an attractive target for novel chemotherapeutics. Based on a survey of genomes from a panel of parasitic nematodes and bacterial organisms and by way of a structure-based amino acid sequence alignment, we derive the topological structure of monoenzyme TPPs and classify them into 3 groups. Comparison of the functional roles of amino acid residues located in the active site for TPPs belonging to different groups reveal nuanced variations. Because current literature on this enzyme family shows a tendency to infer functional roles for individual amino acid residues, we investigated the roles of the strictly conserved aspartate tetrad in TPPs of the nematode Brugia malayi by using a conservative mutation approach. In contrast to aspartate-213, the residue inferred to carry out the nucleophilic attack on the substrate, we found that aspartate-215 and aspartate-428 of BmTPP are involved in the chemistry steps of enzymatic hydrolysis of the substrate. Therefore, we suggest that homology-based inference of functionally important amino acids by sequence comparison for monoenzyme TPPs should only be carried out for each of the 3 groups.-Cross, M., Lepage, R., Rajan, S., Biberacher, S., Young, N. D., Kim, B.-N., Coster, M. J., Gasser, R. B., Kim, J.-S., Hofmann, A. Probing function and structure of trehalose-6-phosphate phosphatases from pathogenic organisms suggests distinct molecular groupings.
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[
Mol Biol Cell,
2005]
Monitoring Editor: Susan Strome BimC kinesins are required for mitotic spindle assembly in a variety of organisms. These proteins are localized to centrosomes, spindle microtubules, and the spindle midzone. We have previously shown that the C. elegans Aurora B kinase AIR-2 is required for the localization of the ZEN-4 kinesin protein to midzone microtubules. To determine whether the association of BimC kinesins with spindle microtubules is also dependent on AIR-2, we examined the expression pattern of BMK-1, a C. elegans BimC kinesin, in wild-type and AIR-2-deficient embryos. BMK-1 is highly expressed in the hermaphrodite gonad and is localized to meiotic spindle microtubules in the newly fertilized embryo. In mitotic embryos, BMK-1 is associated with spindle microtubules from prophase through anaphase, and is concentrated at the spindle midzone during anaphase and telophase. In the absence of AIR-2, BMK-1 localization to meiotic and mitotic spindles is greatly reduced. This is not consequence of loss of ZEN-4 localization as BMK-1 is appropriately localized in ZEN-4 deficient embryos. Furthermore, AIR-2 and BMK-1 directly interact with one another and the C-terminal tail domain of BMK-1 is specifically phosphorylated by AIR-2 in vitro. Together with our previous data, these results suggest that at least one function of the Aurora B kinases is to recruit spindle-associated motor proteins to their sites of action.