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OTU deubiquitinase with linear linkage specificity like OKDB#: 5639
 Symbols: OTULINL Species: human
 Synonyms: NET20, FAM105A  Locus: 5p15.2 in Homo sapiens


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General Comment FAM105A/OTULINL Is a Pseudodeubiquitinase of the OTU-Class that Localizes to the ER Membrane. Ceccarelli DF et al. (2019) Pseudoenzymes have been identified across a diverse range of enzyme classes and fulfill important cellular functions. Examples of pseudoenzymes exist within ubiquitin conjugating and deubiquitinase (DUB) protein families. Here we characterize FAM105A/OTULINL, the only putative pseudodeubiquitinase of the ovarian tumor protease (OTU domain) family in humans. The crystal structure of FAM105A revealed that the OTU domain possesses structural deficiencies in both active site and substrate-binding infrastructure predicted to impair normal DUB function. We confirmed the absence of catalytic function against all ubiquitin linkages and an inability of FAM105A to bind ubiquitin compared with catalytically active FAM105B/OTULIN. FAM105A co-localized with KDEL markers and Lamin B1 at the endoplasmic reticulum (ER) and nuclear envelope, respectively. Accordingly, the FAM105A interactome exhibited significant enrichment in proteins localized to the ER/outer nuclear, Golgi and vesicular membranes. In light of undetectable deubiquitinase activity, we posit that FAM105A/OTULINL functions through its ability to mediate protein-protein interactions.//////////////////

General function
Comment
Cellular localization
Comment
Ovarian function Early embryo development
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Expression regulated by
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Ovarian localization Oocyte
Comment
Follicle stages
Comment
Phenotypes
Mutations 1 mutations

Species: other
Mutation name:
type: null mutation
fertility: infertile - ovarian defect
Comment: What makes a bad egg? Egg transcriptome reveals dysregulation of translational machinery and novel fertility genes important for fertilization. Cheung CT et al. (2019) Egg quality can be defined as the egg ability to be fertilized and subsequently develop into a normal embryo. Previous research has shed light on factors that can influence egg quality. Large gaps however remain including a comprehensive view of what makes a bad egg. Initial development of the embryo relies on maternally-inherited molecules, such as transcripts, deposited in the egg during its formation. Bad egg quality is therefore susceptible to be associated with alteration or dysregulation of maternally-inherited transcripts. We performed transcriptome analysis on a large number (N = 136) of zebrafish egg clutches, each clutch being split to monitor developmental success and perform transcriptome analysis in parallel. We aimed at drawing a molecular portrait of the egg in order to characterize the relation between egg transcriptome and developmental success and to subsequently identify new candidate genes involved in fertility. We identified 66 transcript that were differentially abundant in eggs of contrasted phenotype (low or high developmental success). Statistical modeling using partial least squares regression and genetics algorithm demonstrated that gene signatures from transcriptomic data can be used to predict developmental success. The identity and function of differentially expressed genes indicate a major dysregulation of genes of the translational machinery in poor quality eggs. Two genes, otulina and slc29a1a, predominantly expressed in the ovary and dysregulated in poor quality eggs were further investigated using CRISPR/Cas9 mediated genome editing. Mutants of each gene revealed remarkable subfertility whereby the majority of their eggs were unfertilizable. The Wnt pathway appeared to be dysregulated in the otulina mutant-derived eggs. Here we show that egg transcriptome contains molecular signatures, which can be used to predict developmental success. Our results also indicate that poor egg quality in zebrafish is associated with a dysregulation of (i) the translational machinery genes and (ii) novel fertility genes, otulina and slc29a1a, playing an important role for fertilization. Together, our observations highlight the diversity of the possible causes of egg quality defects and reveal mechanisms of maternal origin behind the lack of fertilization and early embryonic failures that can occur under normal reproduction conditions.//////////////////

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created: July 30, 2019, 4:10 p.m. by: system   email:
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last update: July 30, 2019, 4:12 p.m. by: hsueh    email:



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