scholarly journals RLE-1, an E3 Ubiquitin Ligase, Regulates C. elegans Aging by Catalyzing DAF-16 Polyubiquitination

2007 ◽  
Vol 12 (2) ◽  
pp. 235-246 ◽  
Author(s):  
Wensheng Li ◽  
Beixue Gao ◽  
Sang-Myeong Lee ◽  
Karen Bennett ◽  
Deyu Fang
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
C Elegans

scholarly journals The nuclear ubiquitin ligase adaptor SPOP is a conserved regulator of C9orf72 dipeptide toxicity

2021 ◽  
Author(s):  
Carley Snoznik ◽  
Valentina Medvedeva ◽  
Jelena Mojsilovic-Petrovic ◽  
Paige Rudich ◽  
James Oosten ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Nuclear Localization ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Repeat Expansion ◽  
Dipeptide Repeat Proteins ◽  
C Elegans ◽  
Repeat Proteins ◽  
Lateral Sclerosis ◽  
Dipeptide Repeat

AbstractA hexanucleotide repeat expansion in the C9orf72 gene is the most common cause of inherited amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Unconventional translation of the C9orf72 repeat produces dipeptide repeat proteins (DPRs). Previously, we showed that the DPRs (PR)50 and (GR)50 are highly toxic when expressed in C. elegans and this toxicity depends on nuclear localization of the DPR. In an unbiased genome-wide RNAi screen for suppressors of (PR)50 toxicity, we identified 12 genes that consistently suppressed either the developmental arrest and/or paralysis phenotype evoked by (PR)50 expression. All of these genes have vertebrate homologs and 7/12 contain predicted nuclear localization signals. One of these genes was spop-1, the C. elegans homolog of SPOP, a nuclear localized E3 ubiquitin ligase adaptor only found in metazoans. SPOP is also required for (GR)50 toxicity and functions in a genetic pathway that includes cul-3, which is the canonical E3 ligase partner for SPOP. Genetic or pharmacological inhibition of SPOP in mammalian primary spinal cord motor neurons suppressed DPR toxicity without affecting DPR expression levels. Finally, we find that genetic inhibition of bet-1, the C. elegans homolog of the known SPOP ubiquitination targets BRD2/3/4, suppresses the protective effect of SPOP mutations. Together, these data suggest a model in which SPOP promotes the DPR-dependent ubiquitination and degradation of BRD proteins. We speculate the pharmacological manipulation of this pathway, which is currently underway for multiple cancer subtypes, could also represent a novel entry point for therapeutic intervention to treat C9 FTD/ALS.Significance statementThe G4C2 repeat expansion in the C9orf72 gene is a major cause of Fronto-Temporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). Unusual translation of the repeat sequence produces two highly toxic dipeptide repeat proteins, PRX and GRX, which accumulate in the brain tissue of individuals with these diseases. Here, we show that PR and GR toxicity in both C. elegans and mammalian neurons depends on the E3 ubiquitin ligase adaptor SPOP. SPOP acts through the bromodomain protein BET-1 to mediate dipeptide toxicity. SPOP inhibitors, which are currently being developed to treat SPOP-dependent renal cancer, also protect neurons against DPR toxicity. Our findings identify a highly conserved and ‘druggable’ pathway that may represent a new strategy for treating these currently incurable diseases.

scholarly journals EEL-1, a Hect E3 ubiquitin ligase, controls asymmetry and persistence of the SKN-1 transcription factor in the early C. elegans embryo

Development ◽  
2007 ◽  
Vol 134 (12) ◽  
pp. 2303-2314 ◽  
Author(s):  
B. D. Page ◽  
S. J. Diede ◽  
J. R. Tenlen ◽  
E. L. Ferguson
Keyword(s):  
Transcription Factor ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
C Elegans

scholarly journals Caenorhabditis elegans germline development requires brap-2

2018 ◽  
Author(s):  
Dayana R D'Amora ◽  
Queenie Hu ◽  
Monica Pizzardi ◽  
Terrance Kubiseski
Keyword(s):  
Ubiquitin Ligase ◽  
Brood Size ◽  
Potential Role ◽  
Chromosomal Abnormalities ◽  
E3 Ubiquitin Ligase ◽  
Retention Factor ◽  
Germline Development ◽  
C Elegans ◽  
Mammalian Tissues

Background. Mutations in C. elegans can produce visible and quantifiable defects in morphology, lifespan, and development. BRAP2/IMP (BRCA1-associated binding protein 2) has been characterized as an E3 ubiquitin ligase, a general cytoplasmic retention factor, a potential scaffold protein, and is found to be widely expressed throughout various mammalian tissues, most highly in testes. However, its role in the development or health of these tissues has not been addressed. Results. The focus of this study is to determine the role of BRAP-2 in C. elegans germline development. We determined that brap-2 mutants display defects in germline morphology and a reduction in brood size. We also found that chromosomal abnormalities and embryonic lethality are elevated in brap-2 mutants following DNA damage, suggesting a potential role for BRAP-2 in facilitating DNA repair. Conclusions. Our findings indicate that BRAP-2 is required for C. elegans germline health and identifies a novel role for BRAP-2 in germline development.

scholarly journals Caenorhabditis elegans germline development requires brap-2

2018 ◽  
Author(s):  
Dayana R D'Amora ◽  
Queenie Hu ◽  
Monica Pizzardi ◽  
Terrance Kubiseski
Keyword(s):  
Ubiquitin Ligase ◽  
Brood Size ◽  
Potential Role ◽  
Chromosomal Abnormalities ◽  
E3 Ubiquitin Ligase ◽  
Retention Factor ◽  
Germline Development ◽  
C Elegans ◽  
Mammalian Tissues

Background. Mutations in C. elegans can produce visible and quantifiable defects in morphology, lifespan, and development. BRAP2/IMP (BRCA1-associated binding protein 2) has been characterized as an E3 ubiquitin ligase, a general cytoplasmic retention factor, a potential scaffold protein, and is found to be widely expressed throughout various mammalian tissues, most highly in testes. However, its role in the development or health of these tissues has not been addressed. Results. The focus of this study is to determine the role of BRAP-2 in C. elegans germline development. We determined that brap-2 mutants display defects in germline morphology and a reduction in brood size. We also found that chromosomal abnormalities and embryonic lethality are elevated in brap-2 mutants following DNA damage, suggesting a potential role for BRAP-2 in facilitating DNA repair. Conclusions. Our findings indicate that BRAP-2 is required for C. elegans germline health and identifies a novel role for BRAP-2 in germline development.

scholarly journals The E3 ubiquitin ligase MIB-1 is necessary to form the nuclear halo in C. elegans sperm

2018 ◽  
Author(s):  
Leslie A. Herrera ◽  
Daniel A. Starr
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Forward Genetics ◽  
Eukaryotic Cells ◽  
Nonsense Mutations ◽  
C Elegans ◽  
Nuclear Halo ◽  
Unknown Composition ◽  
Sperm Nuclei ◽  
Mib 1

AbstractUnlike the classical nuclear envelope with two membranes found in other eukaryotic cells, most nematode sperm nuclei are not encapsulated by membranes. Instead, they are surrounded by a nuclear halo of unknown composition. How the halo is formed and regulated is unknown. We used forward genetics to identify molecular lesions behind three classical fer (fertilization defective) mutations that disrupt the ultrastructure of the C. elegans sperm nuclear halo. We found fer-2 and fer-4 alleles to be nonsense mutations in mib-1. fer-3 was caused by a nonsense mutation in eri-3. GFP::MIB-1 was expressed in the germline during early spermatogenesis, but not in mature sperm. mib-1 encodes a conserved E3 ubiquitin ligase homologous to vertebrate Mib1 and Mib2, which function in Notch signaling. However, C. elegans mib-1 has no Notch-related phenotypes. Thus, mib-1 has been co-opted to regulate the formation of the nuclear halo during nematode spermatogenesis.

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