Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Competition between 3’ end maturation and degradation drives snRNA quality control

ABSTRACT: Polymerases and exonucleases act on 3’ ends of nascent RNAs to promote their maturation or degradation but how the balance between these activities is controlled to dictate the fates of cellular RNAs remains poorly understood. Here, we identify a central role for the human DEDD deadenylase TOE1 in distingushing the fates of small nuclear (sn)RNAs of the spliceosome from genome-encoded snRNA variants. We find that TOE1 promotes maturation of all regular RNA polymerase II-transcribed snRNAs of the major and minor spliceosomes by removing post-transcriptional oligo(A)-tails, trimming 3’ ends, and preventing nuclear exosome targeting. By contrast, TOE1 promotes little to no maturation of tested U1 variant snRNAs, which are instead targeted by the nuclear exosome. These observations suggest that TOE1 is positioned at the center of a 3’ end quality control pathway that selectively promotes maturation and stability of regular snRNAs while leaving snRNA variants unprocessed and exposed to degradation in what could be a widespread mechanism of RNA quality control given the large number of non-coding RNAs processed by DEDD deadenylases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE141709 | GEO | 2020/07/13

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

The 3' exonuclease TOE1 selectively processes snRNAs through recognition of Sm complex assembly and 5’ cap trimethylation [global seq]

Project description:Competing exonucleases that promote 3’ end maturation or degradation direct quality control of small non-coding RNAs, but how these enzymes distinguish normal from aberrant RNAs is poorly understood. The Pontocerebellar Hypoplasia 7 (PCH7)-associated 3’ exonuclease TOE1 promotes maturation of canonical small nuclear RNAs (snRNAs). Here, we demonstrate that TOE1 achieves specificity towards canonical snRNAs by recognizing Sm complex assembly and cap trimethylation, two features that distinguish snRNAs undergoing correct biogenesis from other small non-coding RNAs. Indeed, disruption of Sm complex assembly via snRNA mutations or protein depletions obstructs snRNA processing by TOE1, and in vitro snRNA processing by TOE1 is stimulated by a trimethylated cap. An unstable snRNA variant that normally fails to undergo maturation becomes fully processed by TOE1 when its degenerate Sm binding motif is converted into a canonical one. Our findings uncover the molecular basis for how TOE1 distinguishes snRNAs from other small non-coding RNAs and explain how TOE1 promotes maturation specifically of canonical snRNAs undergoing proper processing.

2023-09-06 | GSE240773 | GEO

The 3' exonuclease TOE1 selectively processes snRNAs through recognition of Sm complex assembly and 5’ cap trimethylation [gene specific seq]

2023-09-06 | GSE240772 | GEO

Biallelic mutations in the 3’ exonuclease TOE1 cause Pontocerebellar Hypoplasia Type 7 and result in snRNA processing defects

Project description:Processing of RNA polymerase II-transcribed spliceosomal small nuclear RNAs (snRNAs) initiates with cleavage by the Integrator complex, but the factors that subsequently remove 3’ end extensions from metazoan snRNAs have remained unknown. We studied human families with a unique recessive syndromic constellation of pontocerebellar atrophy with ambiguous genitalia, uncovering biallelic inactivating mutations in TOE1, which encodes a conserved unconventional deadenylase. TOE1 demonstrated tight association with snRNA-protein (snRNP) complexes with specificity for incompletely processed pre-snRNAs containing 3’ end extensions that often included post-transcriptionally added tails. Human cells deficient for TOE1 catalytic activity showed accumulation of 3’-end extended U1, U2, U4 and U5 pre-snRNAs, and TOE1 immuno-isolated from human cells was capable of processing 3’-end extended snRNPs in vitro. The missense mutations identified in patients impaired TOE1 stability and snRNA processing in patient cells, which was associated with defects in splicing. Our findings reveal the cause of a unique brain malformation and uncover a long-sought 3’ exonuclease required for snRNA processing.

2016-12-31 | GSE71536 | GEO

PARN and TOE1 constitute a 3′ end maturation module for nuclear non-coding RNAs

Project description:Poly(A)-specific ribonuclease (PARN) and target of EGR1 protein 1 (TOE1) are nuclear granule-associated deadenylases, whose mutations are linked to multiple human diseases. Here, we applied mTAIL-seq and RNA sequencing (RNA-seq) to systematically identify the substrates of PARN and TOE1 and elucidate their molecular functions. We found that PARN and TOE1 do not modulate the length of mRNA poly(A) tails. Rather, they promote the maturation of nuclear small non-coding RNAs (ncRNAs). PARN and TOE1 act redundantly on some ncRNAs, most prominently small Cajal body-specific RNAs (scaRNAs). scaRNAs are strongly downregulated when PARN and TOE1 are compromised together, leading to defects in small nuclear RNA (snRNA) pseudouridylation. They also function redundantly in the biogenesis of telomerase RNA component (TERC), which shares sequence motifs found in H/ACA box scaRNAs. Our findings extend the knowledge of nuclear ncRNA biogenesis, and they provide insights into the pathology of PARN/TOE1-associated genetic disorders whose therapeutic treatments are currently unavailable.

2018-03-30 | GSE111511 | GEO

yeast U6 3' RACE

Project description:Mpn1 proteins are evolutionarily conserved exonucleases that modify spliceosomal U6 small nuclear RNAs (snRNAs) post-transcriptionally. Mutations in the human MPN1 gene are associated to the genodermatosis Clericuzio-type poikiloderma with neutropenia (PN). Mpn1 deficiency leads to aberrant U6 3M-bM-^@M-^Y end processing and accelerated U6 decay through unknown molecular mechanisms. Here we show that in mpn1M-NM-^T fission yeast cells U6 is barely bound by the protective Lsm2-8 complex, undergoes extensive oligoadenylation and is degraded by the nuclear RNA exonuclease Rrp6 independently of the poly(A) polymerase Cid14/Trf4. Mpn1 processes U6 in a spliceosome-dependent manner, as mutant U6 molecules that fail to join the spliceosome are not substrates for Mpn1. Moreover, human U6atac, the U6-like snRNA of the minor spliceosome, is a novel substrate for hMpn1. We unveil mechanistic details of a new U6 degradation pathway and further corroborate the notion that inefficient canonical and minor pre-mRNA splicing promotes PN. the 3' termini of U6 or tagged-U6 species from the indicated mutant cells were compared to wt yeast strain

2014-08-08 | E-GEOD-60195 | biostudies-arrayexpress

Global 3' RACE in yeast and humans

Project description:Mpn1 proteins are evolutionarily conserved exonucleases that modify spliceosomal U6 small nuclear RNAs (snRNAs) post-transcriptionally. Mutations in the human MPN1 gene are associated to the genodermatosis Clericuzio-type poikiloderma with neutropenia (PN). Mpn1 deficiency leads to aberrant U6 3M-bM-^@M-^Y end processing and accelerated U6 decay through unknown molecular mechanisms. Here we show that in mpn1M-NM-^T fission yeast cells U6 is barely bound by the protective Lsm2-8 complex, undergoes extensive oligoadenylation and is degraded by the nuclear RNA exonuclease Rrp6 independently of the poly(A) polymerase Cid14/Trf4. Mpn1 processes U6 in a spliceosome-dependent manner, as mutant U6 molecules that fail to join the spliceosome are not substrates for Mpn1. Moreover, human U6atac, the U6-like snRNA of the minor spliceosome, is a novel substrate for hMpn1. We unveil mechanistic details of a new U6 degradation pathway and further corroborate the notion that inefficient canonical and minor pre-mRNA splicing promotes PN. The 3' termini of total RNA containing 2'3' cyclic phosphate from Mpn1-proficient and deficient human and yeast cells was sequenced

2014-08-08 | E-GEOD-60197 | biostudies-arrayexpress

FTO controls reversible m6Am RNA methylation during snRNA biogenesis

Project description:Small nuclear RNAs (snRNAs) are core spliceosome components and mediate pre-mRNA splicing. Here we show that snRNAs contain a regulated and reversible nucleotide modification causing them to exist as two different methyl isoforms, m 1 and m 2 , reflecting the methylation state of the adenosine adjacent to the snRNA cap. We find that snRNA biogenesis involves the formation of an initial m 1 isoform with a single-methylated adenosine (2′-O-methyladenosine, Am), which is then converted to a dimethylated m 2 isoform (N 6 ,2′-O-dimethyladenosine, m 6 Am). The relative m 1 and m 2 isoform levels are determined by the RNA demethylase FTO, which selectively demethylates the m 2 isoform. We show FTO is inhibited by the oncometabolite d-2-hydroxyglutarate, resulting in increased m 2 -snRNA levels. Furthermore, cells that exhibit high m 2 -snRNA levels show altered patterns of alternative splicing. Together, these data reveal that FTO controls a previously unknown central step of snRNA processing involving reversible methylation, and suggest that epitranscriptomic information in snRNA may influence mRNA splicing.

2019-02-18 | GSE107872 | GEO

PARN and TOE1 constitute a 3′ end maturation module for nuclear non-coding RNAs

Project description:PARN and TOE1 constitute a 3′ end maturation module for nuclear non-coding RNAs

| PRJNA437251 | ENA

Nopp140-chaperoned 2’-O-methylation of small nuclear RNAs in Cajal bodies ensures splicing fidelity

Project description:Spliceosomal small nuclear RNAs (snRNAs) are modified by small Cajal body (CB) specific ribonucleoproteins (scaRNPs) to ensure snRNP biogenesis and pre-mRNA splicing. However, the function and subcellular site of snRNA modification are largely unknown. We show that CB localization of the protein Nopp140 is essential for concentration of scaRNPs in that nuclear condensate; and that phosphorylation by casein kinase 2 (CK2) at some 80 serines targets Nopp140 to CBs. Transiting through CBs, snRNAs are apparently modified by scaRNPs. Indeed, Nopp140 knockdown-mediated release of scaRNPs from CBs severely compromises 2’-O-methylation of spliceosomal snRNAs, identifying CBs as the site of scaRNP catalysis. Additionally, alternative splicing patterns change indicating that these modifications in U1, U2, U5, and U12 snRNAs safeguard splicing fidelity. Given the importance of CK2 in this pathway, compromised splicing could underlie the mode of action of small molecule CK2 inhibitors currently considered for therapy in cholangiocarcinoma, hematological malignancies, and COVID-19.

2021-07-01 | GSE173171 | GEO

human 3' RACE

Project description:Mpn1 proteins are evolutionarily conserved exonucleases that modify spliceosomal U6 small nuclear RNAs (snRNAs) post-transcriptionally. Mutations in the human MPN1 gene are associated to the genodermatosis Clericuzio-type poikiloderma with neutropenia (PN). Mpn1 deficiency leads to aberrant U6 3M-bM-^@M-^Y end processing and accelerated U6 decay through unknown molecular mechanisms. Here we show that in mpn1M-NM-^T fission yeast cells U6 is barely bound by the protective Lsm2-8 complex, undergoes extensive oligoadenylation and is degraded by the nuclear RNA exonuclease Rrp6 independently of the poly(A) polymerase Cid14/Trf4. Mpn1 processes U6 in a spliceosome-dependent manner, as mutant U6 molecules that fail to join the spliceosome are not substrates for Mpn1. Moreover, human U6atac, the U6-like snRNA of the minor spliceosome, is a novel substrate for hMpn1. We unveil mechanistic details of a new U6 degradation pathway and further corroborate the notion that inefficient canonical and minor pre-mRNA splicing promotes PN. the 3' termini of human U6, U6atac and vtRNA1-1 transcripts from PN patient derived cells and from PN patient cells, compensated with hMPN1 were sequenced.

2014-08-08 | E-GEOD-60196 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data