Rhabditophanes diutinus a parthenogenetic clade IV nematode with dauer larvae.

Comparative studies using non-parasitic model species such as Caenorhabditis elegans, have been very helpful in investigating the basic biology and evolution of parasitic nematodes. However, as phylogenetic distance increases, these comparisons become more difficult, particularly when outside of the nematode clade to which C. elegans belongs (V).

Genomic identification and functional analysis of essential genes in Caenorhabditis elegans.

Background: Essential genes are required for an organism's viability and their functions can vary greatly, spreading across many pathways. Due to the importance of essential genes, large scale efforts have been undertaken to identify the complete set of essential genes and to understand their function. Studies of genome architecture and organization have found that genes are not randomly disturbed in the genome.

Genome-Wide Mutational Signature of the Chemotherapeutic Agent Mitomycin C in Caenorhabditis elegans.

Cancer therapy largely depends on chemotherapeutic agents that generate DNA lesions. However, our understanding of the nature of the resulting lesions as well as the mutational profiles of these chemotherapeutic agents is limited. Among these lesions, DNA interstrand crosslinks are among the more toxic types of DNA damage.

REC-1 and HIM-5 distribute meiotic crossovers and function redundantly in meiotic double-strand break formation in Caenorhabditis elegans.

The Caenorhabditis elegans gene rec-1 was the first genetic locus identified in metazoa to affect the distribution of meiotic crossovers along the chromosome. We report that rec-1 encodes a distant paralog of HIM-5, which was discovered by whole-genome sequencing and confirmed by multiple genome-edited alleles. REC-1 is phosphorylated by cyclin-dependent kinase (CDK) in vitro, and mutation of the CDK consensus sites in REC-1 compromises meiotic crossover distribution in vivo.

Spectrum of variations in dog-1/FANCJ and mdf-1/MAD1 defective Caenorhabditis elegans strains after long-term propagation.

Background: Whole and partial chromosome losses or gains and structural chromosome changes are hallmarks of human tumors. Guanine-rich DNA, which has a potential to form a G-quadruplex (G4) structure, is particularly vulnerable to changes. In Caenorhabditis elegans, faithful transmission of G-rich DNA is ensured by the DOG-1/FANCJ deadbox helicase.

Cyclin B3 and dynein heavy chain cooperate to increase fitness in the absence of mdf-1/MAD1 in Caenorhabditis elegans.

Spindle assembly checkpoint (SAC) ensures genome stability by delaying anaphase onset until all the chromosomes have achieved proper spindle attachment. Once correct attachment has been achieved, SAC must be silenced. In the absence of mdf-1/MAD1, an essential SAC component, Caenorhabditis elegans cannot propagate beyond 3 generations.

The ortholog of the human proto-oncogene ROS1 is required for epithelial development in C. elegans.

The orphan receptor ROS1 is a human proto-oncogene, mutations of which are found in an increasing number of cancers. Little is known about the role of ROS1, however in vertebrates it has been implicated in promoting differentiation programs in specialized epithelial tissues. In this study we show that the C.

C. elegans ring finger protein RNF-113 is involved in interstrand DNA crosslink repair and interacts with a RAD51C homolog.

The Fanconi anemia (FA) pathway recognizes interstrand DNA crosslinks (ICLs) and contributes to their conversion into double-strand DNA breaks, which can be repaired by homologous recombination. Seven orthologs of the 15 proteins associated with Fanconi anemia are functionally conserved in the model organism C. elegans.

Oligoarray comparative genomic hybridization-mediated mapping of suppressor mutations generated in a deletion-biased mutagenesis screen.

Suppressor screens are an invaluable method for identifying novel genetic interactions between genes in the model organism Caenorhabditis elegans. However, traditionally this approach has suffered from the laborious and protracted process of mapping mutations at the molecular level. Using a mutagen known to generate small deletions, coupled with oligoarray comparative genomic hybridization (aCGH), we have identified mutations in two genes that suppress the lethality associated with a mutation of the essential receptor tyrosine kinase rol-3.

A DOG's View of Fanconi Anemia: Insights from C. elegans.

C. elegans provides an excellent model system for the study of the Fanconi Anemia (FA), one of the hallmarks of which is sensitivity to interstrand crosslinking agents. Central to our understanding of FA has been the investigation of DOG-1, the functional ortholog of the deadbox helicase FANCJ.

Synthetic lethality of cohesins with PARPs and replication fork mediators.

Synthetic lethality has been proposed as a way to leverage the genetic differences found in tumor cells to affect their selective killing. Cohesins, which tether sister chromatids together until anaphase onset, are mutated in a variety of tumor types. The elucidation of synthetic lethal interactions with cohesin mutants therefore identifies potential therapeutic targets.

The atm-1 gene is required for genome stability in Caenorhabditis elegans.

The Ataxia-telangiectasia-mutated (ATM) gene in humans was identified as the basis of a rare autosomal disorder leading to cancer susceptibility and is now well known as an important signal transducer in response to DNA damage. An approach to understanding the conserved functions of this gene is provided by the model system, Caenorhabditis elegans. In this paper we describe the structure and loss of function phenotype of the ortholog atm-1.

Allelic ratios and the mutational landscape reveal biologically significant heterozygous SNVs.

The issue of heterozygosity continues to be a challenge in the analysis of genome sequences. In this article, we describe the use of allele ratios to distinguish biologically significant single-nucleotide variants from background noise. An application of this approach is the identification of lethal mutations in Caenorhabditis elegans essential genes, which must be maintained by the presence of a wild-type allele on a balancer.

Specialized chromosomes and their uses in Caenorhabditis elegans.

Research on Caenorhabditis elegans involves the use of a wide range of genetic and molecular tools consisting of chromosomal material captured and modified for specific purposes. These "specialized chromosomes" come in many forms ranging from relatively simple gene deletions to complex rearrangements involving endogenous chromosomes as well as transgenic constructs. In this chapter, we describe the specialized chromosomes that are available in C.

CHL-1 provides an essential function affecting cell proliferation and chromosome stability in Caenorhabditis elegans.

A family of helicases that are important in maintaining genome stability is the iron-sulfur group. Members of this family include DOG-1/FANCJ, RTEL1, XPD and Chl1p/DDX11. In Caenorhabitis elegans, the predicted gene M03C11.

Duplication of cyb-3 (cyclin B3) suppresses sterility in the absence of mdf-1/MAD1 spindle assembly checkpoint component in Caenorhabditis elegans.

mdf-1/MAD1 is a conserved spindle assembly checkpoint component that is essential for the survival of Caenorhabditis elegans. Previously, using a dog-1(gk10)/FANCJ mutator strain, we have isolated a suppressor of mdf-1(gk2) sterility. This suppressor, named such-4, was demonstrated to be a tandem duplication that contained 62 putative protein coding genes.

RTEL-1 enforces meiotic crossover interference and homeostasis.

Meiotic crossovers (COs) are tightly regulated to ensure that COs on the same chromosome are distributed far apart (crossover interference, COI) and that at least one CO is formed per homolog pair (CO homeostasis). CO formation is controlled in part during meiotic double-strand break (DSB) creation in Caenorhabditis elegans, but a second level of control must also exist because meiotic DSBs outnumber COs. We show that the antirecombinase RTEL-1 is required to prevent excess meiotic COs, probably by promoting meiotic synthesis-dependent strand annealing.

Genomic sequence of a mutant strain of Caenorhabditis elegans with an altered recombination pattern.

Background: The original sequencing and annotation of the Caenorhabditis elegans genome along with recent advances in sequencing technology provide an exceptional opportunity for the genomic analysis of wild-type and mutant strains. Using the Illumina Genome Analyzer, we sequenced the entire genome of Rec-1, a strain that alters the distribution of meiotic crossovers without changing the overall frequency. Rec-1 was derived from ethylmethane sulfonate (EMS)-treated strains, one of which had a high level of transposable element mobility.

Synthetic lethal genetic interactions that decrease somatic cell proliferation in Caenorhabditis elegans identify the alternative RFC CTF18 as a candidate cancer drug target.

Somatic mutations causing chromosome instability (CIN) in tumors can be exploited for selective killing of cancer cells by knockdown of second-site genes causing synthetic lethality. We tested and statistically validated synthetic lethal (SL) interactions between mutations in six Saccharomyces cerevisiae CIN genes orthologous to genes mutated in colon tumors and five additional CIN genes. To identify which SL interactions are conserved in higher organisms and represent potential chemotherapeutic targets, we developed an assay system in Caenorhabditis elegans to test genetic interactions causing synthetic proliferation defects in somatic cells.

High-resolution array comparative genomic hybridization analysis reveals unanticipated complexity of genetic deficiencies on chromosome V in Caenorhabditis elegans.

Genomic rearrangements are widely used in Caenorhabditis elegans research but many remain incompletely characterized at the physical level. We have used oligo-array comparative genomic analysis to assess the physical structure of 20 deficiencies and a single duplication of chromosome V. We find that while deletions internal to the chromosome appear simple in structure, terminal deletions are complex, containing duplications in addition to the deletion.

RTEL1 maintains genomic stability by suppressing homologous recombination.

Homologous recombination (HR) is an important conserved process for DNA repair and ensures maintenance of genome integrity. Inappropriate HR causes gross chromosomal rearrangements and tumorigenesis in mammals. In yeast, the Srs2 helicase eliminates inappropriate recombination events, but the functional equivalent of Srs2 in higher eukaryotes has been elusive.

Spectrum of mutational events in the absence of DOG-1/FANCJ in Caenorhabditis elegans.

The Caenorhabditis elegans ortholog of the Fanconi anemia pathway component J (FANCJ) is DOG-1, which is essential for genome stability. Previous studies have shown that disruption of the dog-1 gene generates small deletions of poly-C/poly-G tracts detectable by PCR and results in a mutator phenotype. In this paper, we describe the isolation and characterization of lethal mutations resulting from the loss of dog-1 function.