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TUT1 promotes PDAC progression through Alternative Splicing [3‘-seq]

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a malignant cancer with high lethality rate. In this study, we identify that terminal Uridylyl Transferase 1 (TUT1), a specific terminal uridylyltransferase for U6 snRNA, is required for survival of PDAC, but not for that of normal adult pancreas. Mechanistically, TUT1 uridylylation activity promotes tri-snRNP assembly though facilitating the binding of LSM protein to U6 snRNA. TUT1 deletion leads to global alternative splicing (AS) changes which in turn triggers PDAC cell cycle dysregulation. Here, we reveal a novel function of TUT1 in regulating AS by modulating tri-snRNP levels and identify TUT1 as a potential therapeutic target for the treatment of PDAC.

ORGANISM(S): Mus musculus

PROVIDER: GSE212513 | GEO | 2025/01/11

REPOSITORIES: GEO

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TUT1 promotes PDAC progression through Alternative Splicing [RNA-seq]

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a malignant cancer with high lethality rate. In this study, we identify that terminal Uridylyl Transferase 1 (TUT1), a specific terminal uridylyltransferase for U6 snRNA, is required for survival of PDAC, but not for that of normal adult pancreas. Mechanistically, TUT1 uridylylation activity promotes tri-snRNP assembly though facilitating the binding of LSM protein to U6 snRNA. TUT1 deletion leads to global alternative splicing (AS) changes which in turn triggers PDAC cell cycle dysregulation. Here, we reveal a novel function of TUT1 in regulating AS by modulating tri-snRNP levels and identify TUT1 as a potential therapeutic target for the treatment of PDAC.

2025-01-11 | GSE212514 | GEO

leaf transcriptome comparison between wt and tut1 (salk_087647) -Transcriptome comparison between WT and a mutant impaired in RNA uridylation.

Project description:rs11-10_tut1 - leaf transcriptome comparison between wt and tut1 (salk_087647) - Identification of mRNA targets of the terminal uridylyltransferase TUT1 (AT2G45620) in Arabidopsis thaliana. - Identification of the RNA targets of the terminal uridylyl transferase TUT1 (AT2G45620). Mature rosettte leaf transcriptomes were compared between WT and a tut1 knock-out mutant (SALK_087647). 3 dye-swap - gene knock out

2012-07-12 | E-GEOD-38902 | biostudies-arrayexpress

leaf transcriptome comparison between wt and urt1 (salk_087647) -Transcriptome comparison between WT and a mutant impaired in RNA uridylation.

Project description:rs11-10_urt1 - leaf transcriptome comparison between wt and urt1 (salk_087647) - Identification of mRNA targets of the terminal uridylyltransferase URT1 (AT2G45620) in Arabidopsis thaliana. - Identification of the RNA targets of the terminal uridylyl transferase URT1 (AT2G45620). Mature rosettte leaf transcriptomes were compared between WT and a urt1 knock-out mutant (SALK_087647).

2012-07-13 | GSE38902 | GEO

SILAC APMS anlysis of TSSC4 interactome

Project description:U5 snRNP is a complex particle essential for RNA splicing. U5 snRNPs undergo an intricate biogenesis that ensures that only a fully mature particle assembles into a splicing competent U4/U6•U5 tri-snRNP and enters the splicing reaction. During splicing, U5 snRNP is substantially rearranged and leaves as a U5/PRPF19 post-splicing particle, which requires re-generation before a next round of splicing. Here, we show that a previously uncharacterized protein TSSC4 is a new component of U5 snRNP that promotes tri-snRNP formation. We provide evidence that TSSC4 associates with U5 snRNP chaperones, U5 snRNP and the U5/PRPF19 particle. Specifically, TSSC4 interacts with U5-specific proteins PRPF8, EFTUD2 and SNRNP200. We also identified TSSC4 domains critical for the interaction with U5 snRNP and the PRPF19 complex, as well as for TSSC4 function in tri-snRNP assembly. TSSC4 emerges as a specific chaperone that acts in U5 snRNP de novo biogenesis as well as post-splicing recycling.

2021-06-11 | PXD024929 | Pride

RiboMeth-Seq analysis of purified U6 and U2 snRNAs

Project description:The La-related protein LARP7 has been mainly described as a component of the 7SK small nuclear ribonucleoprotein (snRNP) complex, which negatively regulates RNA polymerase II by sequestering the positive transcription elongation factor b (P-TEFb). In our studies, we discovered a novel, 7SK snRNP-independent function of LARP7. We show that LARP7 interacts with the U6 spliceosomal RNA as well as with the small nucleolar RNAs (snoRNAs) directing the 2'-O-methylations of U6. To investigate the relevance of this interaction, U6 or U2 snRNAs were purified from total RNA by pulldown of biotinylated antisense oligonucleotides and the occurence of 2’-O-methylations was investigated by RiboMeth-seq analysis. A comparison between U6 and U2 snRNA isolated from HEK293 wildtype or LARP7 knockout cell lines revealed that 2’-O-methylations of the U6 snRNA are specifically lost in the absence of LARP7. Alazami syndrome is a form of primary dwarfism associated with mutations in the LARP7 gene. RiboMeth-seq analyses performed with RNA isolated from blood samples of two Alazami patients or healthy parents as well as from B-lymphoblastoid cell lines (B-LCLs) derived from an Alazami patient and from a healthy parent confirmed the impact of mutant LARP7 protein variants on the 2’-O-methylation profile of the U6 snRNA.

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Complexome profiling of nuclear lysates from control and USP39-depleted HeLa cells

Project description:RNA splicing and protein degradation systems allow the functional adaptation of the proteome in response to changing cellular contexts. However, the regulatory mechanisms connecting these processes remain poorly understood. Here, we show that impaired spliceosome assembly caused by USP39 deficiency leads to a pathogenic splicing profile characterized by the use of cryptic 5′ splice sites. To explore the interactions of USP39 and the effect of its depletion in HeLa cells, we performed complexome profiling of nuclear lysates. We observed most USP39 stably integrated into the tri-snRNP complex and there is almost no free nuclear protein. More importantly, the relative abundance of tri-snRNP spliceosome complex was impaired in USP39-depleted cells. As previous reports indicated, USP39 is a regulator of tri-snRNP stability and its depletion decreased the levels of assembled U4/U6.U5 complexes.

2024-09-25 | PXD050738 | Pride

EAPP is essential for tri-snRNP biogenesis and controls cell fate and tumor growth via the alternative splicing of MDM4

Project description:Precursor messenger RNA (pre-mRNA) splicing is catalyzed by the spliceosome, a highly dynamic machinery with sequentially assembled small nuclear ribonucleoproteins (snRNPs) and splicing factors. Aberrant spliceosome composition and function result in the dysregulation of pre-mRNA alternative splicing, which may cause cellular stresses and diseases such as cancer. Here, we identify a splicing factor, E2F-associated phosphoprotein (EAPP), that directly binds to the U4/U6. U5 tri-snRNP and PRPF19 complex. Notably, the C-terminal “bucket” domain in EAPP composed of several beta-sheets is required for its interaction with the tri-snRNP. EAPP is prominently located at Cajal bodies within the nucleus where it colocalizes with the spliceosome. Loss of EAPP impedes the assembly and homeostasis of the tri-snRNP complex in Cajal bodies and increases the frequency of splicing abnormalities, mostly exon skipping. Moreover, EAPP depletion promotes MDM4 exon 6 skipping, which suppresses cell growth and tumor progression via p53 overactivation. Our study demonstrates a previously uncharacterized function of EAPP in spliceosome regulation and reveals that EAPP-mediated alternative splicing of MDM4 is a critical determinant of cell fate and tumor growth.

2024-09-13 | GSE276681 | GEO

Impact of LARP7 depletion on the pA+ transcriptome of HEK293 cells upon heat shock

Project description:The La-related protein LARP7 has been mainly described as a component of the 7SK small nuclear ribonucleoprotein (snRNP) complex, which negatively regulates RNA polymerase II by sequestering the positive transcription elongation factor b (P-TEFb). In our studies, we discovered a novel, 7SK snRNP-independent function of LARP7. We show that LARP7 interacts with the U6 spliceosomal RNA as well as with the small nucleolar RNAs (snoRNAs) directing the 2'-O-methylations of U6. Importantly, in the absence of LARP7, significantly less 2'-O-methylations are deposited on U6 affecting splicing fidelity. Mutations in the LARP7 gene have been associated with the Alazami syndrome, a form of primary dwarfism characterized by intellectual disability. We describe a novel loss-of-function mutation of LARP7 occurring in Alazami patients and detect reduced 2'-O-methylations of U6 in patient-derived samples. Thus, aberrant posttranscriptional RNA modifications of the spliceosomal U6 snRNA may contribute to the development of this severe disease.

2020-02-03 | GSE134813 | GEO

Identification of small RNAs interacting with LARP7

Project description:The La-related protein LARP7 has been mainly described as a component of the 7SK small nuclear ribonucleoprotein (snRNP) complex, which negatively regulates RNA polymerase II by sequestering the positive transcription elongation factor b (P-TEFb). In our studies, we discovered a novel, 7SK snRNP-independent function of LARP7. We show that LARP7 interacts with the U6 spliceosomal RNA as well as with the small nucleolar RNAs (snoRNAs) directing the 2'-O-methylations of U6. Importantly, in the absence of LARP7, significantly less 2'-O-methylations are deposited on U6 affecting splicing fidelity. Mutations in the LARP7 gene have been associated with the Alazami syndrome, a form of primordial dwarfism characterized by intellectual disability. We describe a novel loss-of-function mutation of LARP7 occurring in Alazami patients and detect reduced 2'-O-methylations of U6 in patient-derived samples. Thus, aberrant posttranscriptional RNA modifications of the spliceosomal U6 snRNA may contribute to the development of this severe disease.

2020-02-03 | GSE126592 | GEO

Impact of LARP7 depletion on the transcriptome of HEK293 cells

Project description:The La-related protein LARP7 has been mainly described as a component of the 7SK small nuclear ribonucleoprotein (snRNP) complex, which negatively regulates RNA polymerase II by sequestering the positive transcription elongation factor b (P-TEFb). In our studies, we discovered a novel, 7SK snRNP-independent function of LARP7. We show that LARP7 interacts with the U6 spliceosomal RNA as well as with the small nucleolar RNAs (snoRNAs) directing the 2'-O-methylations of U6. Importantly, in the absence of LARP7, significantly less 2'-O-methylations are deposited on U6 affecting splicing fidelity. Mutations in the LARP7 gene have been associated with the Alazami syndrome, a form of primordial dwarfism characterized by intellectual disability. We describe a novel loss-of-function mutation of LARP7 occurring in Alazami patients and detect reduced 2'-O-methylations of U6 in patient-derived samples. Thus, aberrant posttranscriptional RNA modifications of the spliceosomal U6 snRNA may contribute to the development of this severe disease.

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