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Genome-wide RNAi Screening Identifies pseudouridine synthase DKC1 promotes CRC proliferation through regulating ribosomal proteins expression

ABSTRACT: Colorectal cancer (CRC) with high rate of mortality is one of the most commonly diagnosed cancers in worldwide. Advanced colorectal cancer is often accompanied by malignant proliferation of tumor cells. Further researches on colorectal cancer proliferation to find new targets and develop new therapeutic regimen are an important direction for colorectal cancer treatment. In this study, genome-wide RNAi screening was used to discover the essential genes associated with colorectal cancer cell proliferation. We found DKC1 (dyskerin pseudouridine synthase 1) promoted CRC proliferation through binding and modifying ribosomal proteins (RPL10A, RPL22L1, RPL34, RPS3) mRNA to increase the mRNAs stability and eventually increasing their expression. Besides, DKC1 is highly expressed in colorectal cancer and its aberrantly high expression is associated with poor prognosis of colorectal cancer patients. These results suggest that DKC1 could be a new therapeutic target for colorectal cancer.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Colorectal Cancer Cell

SUBMITTER: guangyan kan

LAB HEAD: Shuai Chen

PROVIDER: PXD018103 | Pride | 2021-02-08

REPOSITORIES: Pride

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Similar Datasets

Genome-wide RNAi Screening Identifies pseudouridine synthase DKC1 promotes CRC proliferation through regulating ribosomal proteins expression

Project description:Colorectal cancer (CRC) with high rate of mortality is one of the most commonly diagnosed cancers in worldwide. Advanced colorectal cancer is often accompanied by malignant proliferation of tumor cells. Further researches on colorectal cancer proliferation to find new targets and develop new therapeutic regimen are an important direction for colorectal cancer treatment. In this study, genome-wide RNAi screening was used to discover the essential genes associated with colorectal cancer cell proliferation. We found DKC1 (dyskerin pseudouridine synthase 1) promoted CRC proliferation through binding and modifying ribosomal proteins (RPL10A, RPL22L1, RPL34, RPS3) mRNA to increase the mRNAs stability and eventually increasing their expression. Besides, DKC1 is highly expressed in colorectal cancer and its aberrantly high expression is associated with poor prognosis of colorectal cancer patients. These results suggest that DKC1 could be a new therapeutic target for colorectal cancer.

2021-04-30 | GSE147348 | GEO

Co-transcriptional pseudouridylation of mRNAs by the H/ACA complex controls translational efficiency [iCLIP]

Project description:Post-transcriptional modifications of mRNA have emerged as novel regulators of gene expression. Pseudouridylation is the most abundant and widespread type of RNA modification in living organisms; however, the biological role of pseudouridine in mRNAs remains poorly understood. Here, we show that the pseudouridine synthase dyskerin associates with RNA polymerase II and is enriched at RNA polymerase II-transcribed genes genome-wide. As part of the H/ACA complex, dyskerin binds to thousands of mRNAs and is responsible for their pseudouridylation, an action that occurs in chromatin and does not appear to require a fully complementary guide RNA. In cells lacking dyskerin, pseudouridylation of mRNAs is reduced, while at the same time, de novo protein production is enhanced, indicating that pseudouridylation of mRNAs by dyskerin interferes with translation. Accordingly, pseudouridylation of an mRNA by dyskerin in vitro results in reduced translation of that mRNA. Moreover, in patients with dyskeratosis congenita caused by inherited mutations in the DKC1 gene, binding between mutated dyskerin and mRNAs is altered and pseudouridylation of mRNAs severely reduced. Our findings reveal a new critical function of the H/ACA complex in directing translation control with important implications for development and disease.

2023-06-26 | GSE211201 | GEO

Co-transcriptional pseudouridylation of mRNAs by the H/ACA complex controls translational efficiency [RNA-seq]

2023-06-26 | GSE211200 | GEO

Co-transcriptional pseudouridylation of mRNAs by the H/ACA complex controls translational efficiency [ChIP-seq]

2023-06-26 | GSE211199 | GEO

NAP-seq Reveals Novel Classes of Structured Noncoding RNAs with Regulatory Functions

Project description:Purpose:Up to 80% of the human genome produces “dark matter” RNAs, most of which are noncapped RNAs (napRNAs). However, determining the functional impacts and metabolism of napRNAs requires the identification of their full-length sequences. Method:Here, by developing a novel method, NAP-seq, to globally profile the full-length sequences of napRNAs at single-nucleotide resolution, we revealed several novel classes of exceptionally structured noncoding RNAs (ncRNAs). Results:We discovered stably expressed linear intron RNAs (sliRNAs), a novel class of snoRNA-intron RNAs (snotrons), a new class of RNAs embedded in miRNA spacers (misRNAs) and thousands of new structured ncRNAs in humans and mice. These new napRNAs undergo dynamic changes in response to various stimuli and differentiation stages. Importantly, we showed that the novel napRNA DINAP interacts with dyskerin pseudouridine synthase 1 (DKC1) to promote cell proliferation by maintaining DKC1 protein stability. Conclusion:Our approach establishes a paradigm for discovering novel classes of ncRNAs with regulatory potency.

2024-02-19 | GSE192632 | GEO

edu-Ψ-seq Reveals snoRNA-guided mRNA Pseudouridylation that Regulates Protein Synthesis [CLIP-seq]

Project description:Purpose:Pseudouridine (Ψ) is the most abundant RNA epigenetic modification and plays vital roles in various biological processes. However, its biogenesis and functions in mRNAs remain elusive. Method:Here, we developed an approach for enriching Ψ sites with deep sequencing (edu-Ψ-seq), which utilizes both exoribonuclease and restriction endonuclease activity to eliminate other nucleosides or reads without Ψ modifications. Results:Using edu-Ψ-seq approach in the dyskerin pseudouridine synthase 1 (DKC1) knockdown cells, we identified that more than 100 pseudouridines could be catalyzed by DKC1 in human mRNAs and non-coding RNAs (ncRNAs). Surprisingly, we discovered, for the first time, 10 pseudouridines in mRNAs might be guided by 11 small nucleolar ncRNAs (snoRNAs). Interestingly, we found that SNORA10 could guide DKC1 protein to induce the pseudouridylation of RPL15 mRNA. Importantly, loss of SNORA10 impaired the protein synthesis of RPL15 and inhibited cell proliferation. Conclusion:Overall, our study not only developed a powerful method for detecting Ψ sites but also uncovered another layer of gene expression regulation that involves crosstalk among snoRNAs, mRNA pseudouridylation and protein synthesis.

2024-10-18 | GSE192381 | GEO

edu-Ψ-seq Reveals snoRNA-guided mRNA Pseudouridylation that Regulates Protein Synthesis

2024-10-18 | GSE190820 | GEO

Study the transcriptional level changes of induced pluripotent stem (iPS) cells from X-linked Dyskeratosis Congenita (DC) Patients

Project description:Dyskeratosis congenita is a bone marrow failure syndrome characterized by the presence of short telomeres at presentation. The X-linked form is caused by mutations in the gene DKC1, encoding the protein dyskerin. Dyskerin is required for in the assembly and stability of telomerase and is also involved in ribosomal RNA (rRNA) processing where it converts specific uridines to pseudouridine. DC is thought to result from failure to maintain tissues, like blood, that are renewed by stem cell activity, suggesting induced pluripotent stem (iPS) cells from X-linked DC patients may provide information about the mechanisms involved. Here we show that in iPS cells with DKC1 mutations Q31E, A353V and ΔL37 telomere maintenance is compromised with short telomere lengths and decreased telomerase activity. The degree to which telomere lengths are affected by expression of telomerase during reprograming, or with ectopic expression of wild type dyskerin varies, with recurrent mutation A353V showing the most severe effect on telomere maintenance. A353V cells but not Q31E or ΔL37 cells, are refractory to correction by incorporation of a single copy of a wild type DKC1 cDNA into the AAVS1 safe harbor locus. None of the mutant cells show decreased pseudouridine levels in rRNA or defective rRNA processing. Finally transcriptome analysis of the iPS cells shows that WNT signaling is significantly decreased in all mutant cells, raising the possibility that defective WNT signaling may contribute to disease pathogenesis.

2015-03-13 | GSE66849 | GEO

Comparison of ribosomes between control and dyskerin-depleted human cells

Project description:Dyskerin is a pseudouridine synthase involved in fundamental cellular processes (including rRNA and snRNA modification and telomere stabilization), whose function is altered in X-linked dyskeratosis congenita and cancer. Dyskerin role in ribosome processing was suggested to underlie the alterations in mRNA translation described in cells lacking dyskerin function. We compared the protein contents of 5 replicates of ribosomal preparations from control or dyskerin-depleted human cells.

2015-05-07 | PXD001274 | Pride

Genome-wide RNAi Screening Identifies pseudouridine synthase DKC1 promotes CRC proliferation through regulating ribosomal proteins expression

Project description:Genome-wide RNAi Screening Identifies pseudouridine synthase DKC1 promotes CRC proliferation through regulating ribosomal proteins expression

| PRJNA613928 | ENA

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