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.

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 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 Regulation of photoprotection gene expression in Chlamydomonas by a putative E3 ubiquitin ligase complex and a homolog of CONSTANS

2019 ◽  
Vol 116 (35) ◽  
pp. 17556-17562 ◽  
Author(s):  
Stéphane T. Gabilly ◽  
Christopher R. Baker ◽  
Setsuko Wakao ◽  
Thien Crisanto ◽  
Katharine Guan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
High Light ◽  
Forward Genetics ◽  
Regulatory Function ◽  
Regulatory Sequences ◽  
Low Light ◽  
Green Algal ◽  
Ubiquitin Ligase Complex

Photosynthetic organisms use nonphotochemical quenching (NPQ) mechanisms to dissipate excess absorbed light energy and protect themselves from photooxidation. In the model green alga Chlamydomonas reinhardtii, the capacity for rapidly reversible NPQ (qE) is induced by high light, blue light, and UV light via increased expression of LHCSR and PSBS genes that are necessary for qE. Here, we used a forward genetics approach to identify SPA1 and CUL4, components of a putative green algal E3 ubiquitin ligase complex, as critical factors in a signaling pathway that controls light-regulated expression of the LHCSR and PSBS genes in C. reinhardtii. The spa1 and cul4 mutants accumulate increased levels of LHCSR1 and PSBS proteins in high light, and unlike the wild type, they express LHCSR1 and exhibit qE capacity even when grown in low light. The spa1-1 mutation resulted in constitutively high expression of LHCSR and PSBS RNAs in both low light and high light. The qE and gene expression phenotypes of spa1-1 are blocked by mutation of CrCO, a B-box Zn-finger transcription factor that is a homolog of CONSTANS, which controls flowering time in plants. CONSTANS-like cis-regulatory sequences were identified proximal to the qE genes, consistent with CrCO acting as a direct activator of qE gene expression. We conclude that SPA1 and CUL4 are components of a conserved E3 ubiquitin ligase that acts upstream of CrCO, whose regulatory function is wired differently in C. reinhardtii to control qE capacity via cis-regulatory CrCO-binding sites at key photoprotection genes.

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 Retroviral insertional mutagenesis implicates E3 ubiquitin ligase RNF168 in the control of cell proliferation and survival

2017 ◽  
Vol 37 (4) ◽  
Author(s):  
Aytug Kizilors ◽  
Mark R. Pickard ◽  
Cathleen E. Schulte ◽  
Kiren Yacqub-Usman ◽  
Nicola J. McCarthy ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Line ◽  
Cell Fate ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Nuclear Bodies ◽  
Forward Genetics ◽  
Dna Breaks ◽  
Control Of Gene Expression ◽  
Pml Nuclear Bodies

The E3 ubiquitin ligase RNF168 is a ring finger protein that has been previously identified to play an important regulatory role in the repair of double-strand DNA breaks. In the present study, an unbiased forward genetics functional screen in mouse granulocyte/macrophage progenitor cell line FDCP1 has identified E3 ubiquitin ligase RNF168 as a key regulator of cell survival and proliferation. Our data indicate that RNF168 is an important component of the mechanisms controlling cell fate, not only in human and mouse haematopoietic growth factor dependent cells, but also in the human breast epithelial cell line MCF-7. These observations therefore suggest that RNF168 provides a connection to key pathways controlling cell fate, potentially through interaction with PML nuclear bodies and/or epigenetic control of gene expression. Our study is the first to demonstrate a critical role for RNF168 in the mechanisms regulating cell proliferation and survival, in addition to its well-established role in DNA repair.

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