Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.27.1 (RNase)
 16,360 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the human telomerase RNA component (hTR), the telomerase ribonucleoprotein component dyskerin (DKC1) and the poly(A) RNase (PARN) can lead to reduced levels of hTR and to dyskeratosis congenita (DC). However, the enzymes and mechanisms responsible for hTR degradation are unknown. We demonstrate that defects in dyskerin binding lead to hTR degradation by PAPD5-mediated oligoadenylation, which promotes 3'-to-5' degradation by EXOSC10, as well as decapping and 5'-to-3' decay by the cytoplasmic DCP2 and XRN1 enzymes. PARN increased hTR levels by deadenylating hTR, thereby limiting its degradation by EXOSC10. Telomerase activity and proper hTR localization in dyskerin- or PARN-deficient cells were rescued by knockdown of DCP2 and/or EXOSC10. Prevention of hTR RNA decay also led to a rescue of localization of DC-associated hTR mutants. These results suggest that inhibition of RNA decay pathways might be a useful therapy for some telomere pathologies.
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PMID:Inhibition of telomerase RNA decay rescues telomerase deficiency caused by dyskerin or PARN defects. 2695 Mar 71

Nucleolin (NCL) is a major component of the cell nucleolus, which has the ability to rapidly shuttle to several other cells' compartments. NCL plays important roles in a variety of essential functions, among which are ribosome biogenesis, gene expression, and cell growth. However, the precise mechanisms underlying NCL functions are still unclear. Our study aimed to provide new information on NCL functions via the identification of its nuclear interacting partners. Using an interactomics approach, we identified 140 proteins co-purified with NCL, among which 100 of them were specifically found to be associated with NCL after RNase digestion. The functional classification of these proteins confirmed the prominent role of NCL in ribosome biogenesis and additionally revealed the possible involvement of nuclear NCL in several pre-mRNA processing pathways through its interaction with RNA helicases and proteins participating in pre-mRNA splicing, transport, or stability. NCL knockdown experiments revealed that NCL regulates the localization of EXOSC10 and the amount of ZC3HAV1, two components of the RNA exosome, further suggesting its involvement in the control of mRNA stability. Altogether, this study describes the first nuclear interactome of human NCL and provides the basis for further understanding the mechanisms underlying the essential functions of this nucleolar protein.
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PMID:Nuclear Functions of Nucleolin through Global Proteomics and Interactomic Approaches. 2704 34

Growing mammalian oocytes accumulate substantial amounts of RNA, most of which is degraded during subsequent meiotic maturation. The growth-to-maturation transition begins with germinal vesicle or nuclear envelope breakdown (GVBD) and is critical for oocyte quality and early development. The molecular machinery responsible for the oocyte transcriptome transition remains unclear. Here, we report that an exosome-associated RNase, EXOSC10, sculpts the transcriptome to facilitate the growth-to-maturation transition of mouse oocytes. We establish an oocyte-specific conditional knockout of Exosc10 in mice using CRISPR/Cas9 which results in female subfertility due to delayed GVBD. By performing multiple single oocyte RNA-seq, we document dysregulation of several types of RNA, and the mRNAs that encode proteins important for endomembrane trafficking and meiotic cell cycle. As expected, EXOSC10-depleted oocytes have impaired endomembrane components including endosomes, lysosomes, endoplasmic reticulum and Golgi. In addition, CDK1 fails to activate, possibly due to persistent WEE1 activity, which blocks lamina phosphorylation and disassembly. Moreover, we identified rRNA processing defects that cause higher percentage of developmentally incompetent oocytes after EXOSC10 depletion. Collectively, we propose that EXOSC10 promotes normal growth-to-maturation transition in mouse oocytes by sculpting the transcriptome to degrade RNAs encoding growth-phase factors and, thus, support the maturation phase of oogenesis.
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PMID:EXOSC10 sculpts the transcriptome during the growth-to-maturation transition in mouse oocytes. 3231 33

Nucleotide repeat expansions in the C9orf72 gene cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeat RNA accumulates within RNA foci and is also translated into toxic dipeptide repeat proteins (DPR). The mechanism of repeat RNA accumulation, however, remains unclear. The RNA exosome complex is a multimeric ribonuclease involved in degradation of defective RNA. Here, we uncover the RNA exosome as a major degradation complex for pathogenic C9orf72-derived repeat RNA. Knockdown of EXOSC10, the catalytic subunit of the complex, enhanced repeat RNA and DPR protein expression levels. RNA degradation assays confirmed that EXOSC10 can degrade both sense and antisense repeats. Furthermore, EXOSC10 reduction increased RNA foci and repeat transcripts in patient-derived cells. Cells expressing toxic poly-GR or poly-PR proteins accumulate a subset of small nucleolar RNA precursors, which are physiological substrates of EXOSC10, as well as excessive repeat RNA, indicating that arginine-rich DPR proteins impair the intrinsic activity of EXOSC10. Collectively, arginine-rich DPR-mediated impairment of EXOSC10 and the RNA exosome complex compromises repeat RNA metabolism and may thus exacerbate C9orf72-FTLD/ALS pathologies in a vicious cycle.
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PMID:The RNA exosome complex degrades expanded hexanucleotide repeat RNA in C9orf72 FTLD/ALS. 3283 Aug 71