| 2000 |
The SKI4 gene is identical to CSL4, which encodes a core component of the exosome. A point mutation in the putative RNA-binding domain of Csl4p (ski4-1, G253E) strongly impairs 3'-to-5' mRNA degradation without affecting exosome function in rRNA or snRNA processing, demonstrating that distinct exosome functions can be genetically separated and that the RNA-binding domain of Csl4p has a specific role in mRNA degradation. |
Genetic epistasis, allele identification, mRNA half-life assays, RNA processing assays in S. cerevisiae |
Molecular and cellular biology |
High |
11027292
|
| 2001 |
The human protein hCsl4p is a component of the human exosome (PM/Scl complex), as evidenced by autoantibodies in patients with idiopathic inflammatory myopathy and PM/Scl overlap syndrome targeting hCsl4p along with other exosome subunits. |
ELISA and Western blotting with affinity-purified recombinant hCsl4p using patient sera |
Arthritis research |
Medium |
11879549
|
| 2002 |
Human hCsl4p directly interacts with exosome subunits hRrp42p and hRrp46p, and these protein-protein interactions are required for hCsl4p's association with the exosome complex in vivo. Mutants of hCsl4p that fail to interact with either hRrp42p or hRrp46p cannot associate with the exosome. |
Mammalian two-hybrid assay, GST pull-down, co-immunoprecipitation from cell lysates |
Journal of molecular biology |
High |
11812149
|
| 2005 |
Crystal structures of archaeal exosome isoforms revealed that Csl4 (along with Rrp4) forms a trimeric cap on top of the hexameric RNase-PH domain ring. The S1 domains of this cap and a 'neck' region of the RNase-PH ring form an RNA entry pore that restricts access to unstructured RNA, explaining processive degradation of unstructured RNA and the requirement for cofactors to degrade structured RNA. |
X-ray crystallography of archaeal exosome, tungstate soaks, structural and mutational analysis |
Molecular cell |
High |
16285927
|
| 2007 |
Crystal structure of the Sulfolobus solfataricus nine-subunit exosome with bound RNA substrate shows that RNA binds both at the active site and at the opposite side in the narrowest constriction of the central channel, establishing that Csl4 contributes to the RNA-binding cap that channels substrate through the central pore for processive degradation. |
X-ray crystallography at 1.6 Å and 2.3 Å resolution with RNA-bound complex |
EMBO reports |
High |
17380186
|
| 2008 |
In yeast (Csl4/Ski4p), the zinc-ribbon domain of Csl4 is required for exosome-mediated mRNA decay but none of its domains are individually required for viability, indicating that specific structural domains contribute to specific exosome functions. |
Domain deletion analysis in S. cerevisiae with mRNA decay assays |
Nature structural & molecular biology |
High |
19060898
|
| 2008 |
Archaeal Csl4, when incorporated into the nine-subunit exosome (Csl4-exosome), enhances efficient degradation of structured RNA substrates (tRNA, heteropolymeric transcripts) by the catalytic Rrp41-Rrp42 hexamer. Csl4 itself has no hydrolytic RNase activity alone or in context of the complex, but strong substrate binding mediated by Csl4 is important for phosphorolysis. |
In vitro reconstitution of archaeal exosome complexes with different subunit compositions, RNase activity assays under varied conditions |
Biochemistry |
High |
19053279
|
| 2010 |
Archaeal Csl4 confers different substrate specificity to the exosome compared with Rrp4: the Csl4-exosome degrades RNA with an A-poor 3'-end with higher efficiency, while the Rrp4-exosome strongly prefers poly(A) RNA. This establishes that Csl4 and Rrp4 have distinct functional roles in substrate selection. |
In vitro RNA degradation assays with reconstituted archaeal exosome complexes containing defined Rrp4 or Csl4 caps |
FEBS letters |
High |
20488184
|
| 2010 |
The Csl4-exosome (archaeal) interacts with the archaea-specific DnaG subunit, which binds to the Csl4-exosome but not to the Rrp4-exosome, showing that Csl4 mediates DnaG recruitment to the exosome complex. |
In vitro binding assays with reconstituted complexes; co-purification |
FEBS letters |
Medium |
20488184
|
| 2011 |
Human hCsl4p functionally rescues the null phenotype of yeast ski4Δ cells and partially complements the superkiller phenotype of ski4-1 mutation. The equivalent point mutation G152E in hCsl4p (corresponding to yeast ski4-1 G253E) impairs hCsl4p activity. hCsl4p physically interacts with the Dis3p exonuclease of the yeast exosome despite lacking the N-terminal third of Ski4p. This N-terminal third of Ski4p is dispensable for RNA degradation function. |
Yeast complementation assays, superkiller phenotype analysis, co-immunoprecipitation with Dis3p, site-directed mutagenesis |
Yeast |
High |
22068837
|
| 2013 |
The archaeal DnaG protein binds to the Csl4-exosome but not to the Rrp4-exosome of Sulfolobus solfataricus. DnaG is a poly(A)-binding protein that enhances degradation of adenine-rich transcripts specifically in the context of the Csl4-exosome, functioning as a second poly(A)-binding subunit in the heteromeric RNA-binding cap. |
In vitro binding assays, RNA degradation assays with reconstituted exosome complexes, poly(A)-binding assays |
RNA biology |
Medium |
23324612
|
| 2014 |
Archaeal Csl4 is involved in the interaction with the archaea-specific DnaG subunit of the exosome complex. In the archaeal exosome, Rrp4 confers poly(A) specificity while Csl4 mediates DnaG association. Both Rrp4 and Csl4 form a variable RNA-binding trimeric cap on the hexameric ring. |
Biochemical reconstitution, subunit interaction analysis, in vitro RNA degradation assays |
Wiley interdisciplinary reviews. RNA |
Medium |
24789718
|
| 2021 |
A homozygous missense variant p.Ser35Leu in EXOSC1 reduces EXOSC1 protein levels and reduces the EXO9 (nine-subunit exosome) complex abundance in patient cells, establishing that EXOSC1 is required for stable EXO9 complex formation in human cells and that loss of EXOSC1 function causes pontocerebellar hypoplasia type 1. |
Immunoblotting, blue native PAGE, exome sequencing, in silico mutagenesis of protein structure |
Clinical genetics |
Medium |
33463720
|
| 2021 |
EXOSC1 cleaves single-stranded DNA preferentially at C sites in vitro, acts as an endogenous source of mutations via C>A transversions in human kidney renal clear cell carcinoma cells, and sensitizes these cells to PARP inhibitors. |
In vitro ssDNA cleavage assays, statistical correlation of EXOSC1 expression with mutation spectra in KIRC, cell sensitivity assays with PARP inhibitors |
eLife |
Medium |
34159897
|
| 2023 |
The EXOSC1 variant p.Arg183Trp causes a slow-growth phenotype in yeast when expressed as the human variant, while EXOSC1-Ser35Leu is lethal in the same model, demonstrating impaired exosome function. Protein levels of both EXOSC1 variants are reduced compared with wild-type when expressed in budding yeast, confirming pathogenicity through reduced protein stability. |
Yeast complementation and growth assays, Western blotting for protein levels in yeast |
American journal of medical genetics. Part A |
Medium |
37024942
|
| 2023 |
Exosc1 null mouse embryos implant and form an egg cylinder but are developmentally delayed and fail to initiate gastrulation by embryonic day 7.5, demonstrating that EXOSC1 is essential for early mammalian development at the gastrulation stage. |
Homozygous knockout mouse embryo analysis, embryo recovery at defined developmental stages, morphological and lineage-specification analysis |
Gene expression patterns |
Medium |
37940010
|
| 2025 |
CARM1 methylates arginine 6 of EXOSC1, protecting it from proteasome-mediated degradation. This post-translational methylation event enhances RNA exosome activity, attenuates nuclear export of retroelement transcripts by the mRNA export pathway, and thereby suppresses the viral mimicry response and antitumor immunity. |
Mass spectrometry identification of methylation site, proteasome inhibitor assays, RNAseq, functional pathway analysis in tumor cell lines |
Science translational medicine |
Medium |
40203080
|
| 2025 |
Using inducible CRISPR/Cas9 knockouts in mouse embryonic stem cells, Exosc1 is identified as the terminally incorporated cap subunit in a sequential RNA exosome assembly pathway (initiated by Exosc2, Exosc4, and Exosc7). Unlike other structural subunits, Exosc1 is dispensable for cell viability, revealing that the RNA exosome has a modular, functionally resilient architecture. Orphan exosome subunits are degraded by the ubiquitin-proteasome system. |
Inducible dual-guide CRISPR/Cas9 knockout system in mESCs, proteomics, assembly hierarchy analysis |
bioRxivpreprint |
Medium |
bio_10.1101_2025.03.14.643291
|