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Nature Genetics,
2002]
DNA replication through mononucleotide runs is frequently associated with slippage of DNA polymerase, leading to the insertion or deletion of a small number of base pairs. A new study shows that, in the absence of DOG-1, a putative helicase, long pol(dG/C) runs are associated with deletions that extend into flanking DNA sequences. This mutational signature may be related to the ability of poly(dG) to form secondary structures such as G-quadruplex DNA, and may contribute to the genomic instability of tumor cells.
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Adv Exp Med Biol,
2013]
The oocyte-to-embryo transition refers to the process whereby a fully grown, relatively quiescent oocyte undergoes maturation, fertilization, and is converted into a developmentally active, mitotically dividing embryo, arguably one of the most dramatic transitions in biology. This transition occurs very rapidly in Caenorhabditis elegans, with fertilization of a new oocyte occurring every 23 min and the first mitotic division occurring 45 min later. Molecular events regulating this transition must be very precisely timed. This chapter reviews our current understanding of the coordinated temporal regulation of different events during this transition. We divide the oocyte-to-embryo transition into a number of component processes, which are coordinated primarily through the MBK-2 kinase, whose activation is intimately tied to completion of meiosis, and the OMA-1/OMA-2 proteins, whose expression and functions span multiple processes during this transition. The oocyte-to-embryo transition occurs in the absence of de novo transcription, and all the factors required for the process, whether mRNA or protein, are already present within the oocyte. Therefore, all regulation of this transition is posttranscriptional. The combination of asymmetric partitioning of maternal factors, protein modification-mediated functional switching, protein degradation, and highly regulated translational repression ensure a smooth oocyte-to-embryo transition. We will highlight protein degradation and translational repression, two posttranscriptional processes which play particularly critical roles in this transition.
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Curr Top Dev Biol,
2015]
In Caenorhabditis elegans, the first zygotic transcription can be detected in the 4-cell stage C. elegans embryo, a little over 2h after fertilization. However, early development until the onset of gastrulation at approximately the 28-cell stage takes place normally even in the absence of zygotic transcription. Therefore, posttranslational and posttranscriptional regulation of the maternal proteins and mRNAs, respectively, that are loaded into the developing oocytes is sufficient to direct development prior to gastrulation. Protein phosphorylation is extensively used throughout the C. elegans maternal-to-zygotic transition (MZT): (1) for maternal protein activation, (2) for coordination of the meiotic and mitotic cell cycle, (3) to mark specific proteins for degradation, and/or (4) to switch the biochemical activity of specific proteins. Maternally loaded mRNAs are regulated primarily by a set of maternal RNA-binding proteins (RBPs), each of which binds to sometimes overlapping target sequences within the mRNA 3'UTRs and either promotes or inhibits translation. Most maternal transcripts are uniformly distributed throughout the embryo but specific transcripts are translated only in certain blastomeres. This control is achieved by the asymmetric distribution of the maternal RBPs, such that the blastomere-specific constellation of RBPs present, and their relative levels, determines the translational readout for their target transcripts. In certain well-studied cases, such as the specification of the sole endodermal precursor in the 8-cell embryo, the maternal transcripts and proteins along with their directly targeted zygotic genes have been identified.
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Exp Gerontol,
2006]
Caenorhabditis elegans has been used to model aspects of a number of age-associated neurodegenerative diseases, including Alzheimer''s, Parkinson''s and Huntington''s diseases. These models have typically involved the transgenic expression of disease-associated human proteins. Here I describe my laboratory''s specific experience engineering C. elegans models of Alzheimer''s disease, and give a general consideration of the advantages and disadvantages of these C. elegans models. The type of insights that might be gained from using these (relatively) simple models are highlighted. In particular, I consider the potential these models have for uncovering common and unique fundamental toxic mechanisms underlying human neurodegenerative diseases.
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Curr Biol,
2001]
When meiotic cells complete S phase, homologous chromosomes pair, synapse and undergo recombination. A checkpoint protein is somehow required for meiotic chromosome pairing in C. elegans, thus providing a direct link between S phase and the rest of the meiotic program.
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Toxins (Basel),
2016]
Staphylococcus aureus is an opportunistic pathogen and the leading cause of a wide range of severe clinical infections. The range of diseases reflects the diversity of virulence factors produced by this pathogen. To establish an infection in the host, S. aureus expresses an inclusive set of virulence factors such as toxins, enzymes, adhesins, and other surface proteins that allow the pathogen to survive under extreme conditions and are essential for the bacteria's ability to spread through tissues. Expression and secretion of this array of toxins and enzymes are tightly controlled by a number of regulatory systems. S. aureus is also notorious for its ability to resist the arsenal of currently available antibiotics and dissemination of various multidrug-resistant S. aureus clones limits therapeutic options for a S. aureus infection. Recently, the development of anti-virulence therapeutics that neutralize S. aureus toxins or block the pathways that regulate toxin production has shown potential in thwarting the bacteria's acquisition of antibiotic resistance. In this review, we provide insights into the regulation of S. aureus toxin production and potential anti-virulence strategies that target S. aureus toxins.
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WormBook,
2007]
Because of their free-living life cycle alternatives, Strongyloides and related nematode parasites may represent the best models for translating C. elegans science to the study of nematode parasitism. S. stercoralis, a significant pathogen of humans, can be maintained in laboratory dogs and gerbils. Biosafety precautions necessary for work with S. stercoralis, though unfamiliar to many C. elegans researchers, are straightforward and easily accomplished. Although specialized methods are necessary for large-scale culture of the free-living stages of S. stercoralis, small-scale cultures for experimental purposes may be undertaken using minor modifications of standard C. elegans methods. Similarly, the morphological similarities between C. elegans and the free-living stages of S. stercoralis allow investigational methods such as laser cell ablation and DNA transformation by gonadal microinjection to be easily adapted from C. elegans to S. stercoralis. Comparative studies employing these methods have yielded new insights into the neuronal control of the infective process in parasites and its similarity to regulation of dauer development in C. elegans. Furthermore, we have developed a practical method for transient transformation of S. stercoralis with vector constructs having various tissue- and cell-specific expression patterns and have assembled these into a modular vector kit for distribution to the community.
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Ann Pharm Fr,
2006]
The Nematode Caenorhabditis elegans (C. elegans) is an established model increasingly used for studying human disease pathogenesis. C. elegans models are based on the mutagenesis of human disease genes conserved in this Nematode or on the transgenesis with disease genes not conserved in C. elegans. Genetic examinations will give new insights on the cellular and molecular mechanisms that are altered in some neurodegenerative diseases like Duchenne''s muscular dystrophy, Huntington''s disease and Alzheimer''s disease. C. elegans may be used for primary screening of new compounds that may be used as drugs in these diseases.
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Mol Cell,
2004]
Applying a combination of innovative approaches to understanding neuronal gene regulation in C. elegans, an article in the latest Developmental Cell (Wenick and Hobert, 2004) gives hope that reading the genome''s transcriptional regulatory code may one day be possible.
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Front Biosci,
2004]
Alzheimer''s disease (AD) is affecting more people every year due to the increase in elderly population. This disease is characterized by senior plaques, containing aggregated amyloid beta peptide (A beta), and neurofibrillary tangles in the AD brains. The A beta depositions are thought to increase in cellular oxidative stress, which subsequently produces neuronal cell death in the patient s brain, causing loss of memory and, in the latter stages, dementia. Diverse models have been established to test this, "Amyloid Toxicity Hypothesis of AD". Among these, the use of the nematode Caenorhabditis elegans has some advantages. This invertebrate has its entire genome known, as well as numerous gene homologues to those seen in humans. In relationship with the cell model, the nematode gives the benefit of an organismal view of the disease. The nematode''s short life span proves useful, when compared with that of mice, allowing mechanistic studies of the disease and pharmacological treatments. Alongside with other laboratories, we have used this in vivo model to correlate the Abeta expression with its toxicity through the observance of the organism''s behavior to provide a better understanding of the cellular processes underlining AD.