Ectopically expressed pNO40 suppresses ribosomal RNA synthesis by inhibiting UBF-dependent transcription activation

Lin, Yen-Ming; Chu, Pao‐Hsien; Ouyang, Pin

doi:10.1016/j.bbrc.2019.06.057

Cited by 7 publications

(6 citation statements)

References 19 publications

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“…RNA Pol I and UBF are essential members of the pre-initiation complex that promotes the initiation of rDNA promoter transcription (30). Disrupting the binding ability of UBF and RNA Pol I to the rDNA promoter decreases rDNA transcription and rRNA synthesis (31). Previous studies have reported that TP is a known inhibitor of RNA polymerase I; therefore, it was hypothesized that the inhibition of rRNA synthesis by TP in the present study was a result of suppression of RNA Pol I.…”

Section: Discussionmentioning

confidence: 71%

Triptolide interrupts rRNA synthesis and induces the RPL23‑MDM2‑p53 pathway to repress lung cancer cells

Wang

Zhang

et al. 2020

Oncol Rep

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Lung cancer has one of the highest mortalities of any cancer worldwide. Triptolide (TP) is a promising tumor suppressor extracted from the Chinese herb Tripterygium wilfordii. Our previous proteomics analysis revealed that TP significantly interfered with the ribosome biogenesis pathway; however, the underlying molecular mechanism remains poorly understood. The aim of the present study was to determine the molecular mechanism of TP's anticancer effect by investigating the association between ribosomal stress and p53 activation. It was found that TP induces nucleolar disintegration together with RNA polymerase I (Pol I) and upstream binding factor (UBF) translocation. TP interrupted ribosomal (r)RNA synthesis through inhibition of RNA Pol I and UBF transcriptional activation. TP treatment increased the binding of ribosomal protein L23 (RPL23) to mouse double minute 2 protein (MDM2), resulting in p53 being released from MDM2 and stabilized. Activation of p53 induced apoptosis and cell cycle arrest by enhancing the activation of p53 upregulated modulator of apoptosis, caspase 9 and caspase 3, and suppressing BCL2. In vivo experiments showed that TP significantly reduced xenograft tumor size and increased mouse body weight. Immunohistochemical assays confirmed that TP significantly increased the p53 level and induced nucleolus disintegration, during which nucleolin distribution moved from the nucleolus to the nucleoplasm, and RPL23 clustered at the edge of the cell membrane. Therefore, it was proposed that TP induces ribosomal stress, which leads to nucleolus disintegration, and inhibition of rRNA transcription and synthesis, resulting in increased binding of RPL23 with MDM2. Consequently, p53 is activated, which induces apoptosis and cell cycle arrest.

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Section: Discussionmentioning

confidence: 71%

Triptolide interrupts rRNA synthesis and induces the RPL23‑MDM2‑p53 pathway to repress lung cancer cells

Wang

Zhang

et al. 2020

Oncol Rep

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“…ZCCHC17 has been studied in non-neuronal tissues and has been shown to play a diverse range of regulatory roles in RNA processing (Lin et al, 2017; Lin et al, 2019). Its function has not been previously studied in human neurons, and it may exert its regulatory effect through its CCHC-type zinc finger domain, the RNA-binding capacity of its S1 domain, or via its interactions with proteins involved in RNA processing ( Figure 1A ; note that it may be less likely to act as a classical zinc finger transcription factor as it only contains a single zinc finger domain (Lambert et al, 2018)).…”

Section: Resultsmentioning

confidence: 99%

“…91 unique binding partners for ZCCHC17 were identified in human iPSC-derived neurons ( Figure 1D, Supplemental Table S1 ). Seven of these proteins have been previously identified as ZCCHC17 binding partners in non-neuronal cells, including PNN (Chang et al, 2003; Huttlin et al, 2017; Lin et al, 2017), UBTF (Lin et al, 2019), JMJD6, FTL, SRRM2, NOS1AP, and RNPS1 (Huttlin et al, 2017), suggesting conserved interactions across cell types. Several of ZCCHC17’s binding partners have previously been highlighted for their importance in AD, including those involved in autophagy/lysosome function (AP2A1, AP2A2, ATP6V1A) (Raj et al, 2018; Wang et al, 2021a), stress granules (PABPC1, PABPC3) (Anderson and Kedersha, 2008), TIA-1 interactors (RPL6, RPL7, RPL7A, RPL10A, RPL13, RPS4X, AP2A1, AP2B1, ATP6V1A, PURA, SYNCRIP, PABPC1) (Vanderweyde et al, 2016), and RNA binding (ACIN1, SNRPB2) in the presence of AD pathology (Apicco et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

“…ZCCHC17 contains an S1 RNA binding domain, zinc-finger (CCHC) domain, and 2 nuclear localization signals, and northern blot analysis has shown that its transcripts are found throughout the body, with strongest expression in the normal brain, heart, skeletal muscle, and thymus (Chang et al, 2003). Although the exact function of ZCCHC17 is unknown, recent evidence showing that it is involved in mRNA (Lin et al, 2017) and rRNA (Lin et al, 2019) processing have led some to suggest that it may help coordinate a wide range of homeostatic functions in the cell (Lin et al, 2017). Our prior work demonstrated that ZCCHC17 protein is expressed in neurons and declines early in AD brain tissue before significant gliosis or neuronal loss, while knockdown of ZCCHC17 in rat neuronal cultures leads to dysregulation of a wide range of genes, including synaptic genes (Tomljanovic et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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ZCCHC17 modulates neuronal RNA splicing and supports cognitive resilience in Alzheimer’s disease

Bartosch

Youth

Hansen

et al. 2023

Preprint

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ZCCHC17 is a putative master regulator of synaptic gene dysfunction in Alzheimer's Disease (AD), and ZCCHC17 protein declines early in AD brain tissue, before significant gliosis or neuronal loss. Here, we investigate the function of ZCCHC17 and its role in AD pathogenesis. Co-immunoprecipitation of ZCCHC17 followed by mass spectrometry analysis in human iPSC-derived neurons reveals that ZCCHC17's binding partners are enriched for RNA splicing proteins. ZCCHC17 knockdown results in widespread RNA splicing changes that significantly overlap with splicing changes found in AD brain tissue, with synaptic genes commonly affected. ZCCHC17 expression correlates with cognitive resilience in AD patients, and we uncover an APOE4 dependent negative correlation of ZCCHC17 expression with tangle burden. Furthermore, a majority of ZCCHC17 interactors also co-IP with known tau interactors, and we find significant overlap between alternatively spliced genes in ZCCHC17 knockdown and tau overexpression neurons. These results demonstrate ZCCHC17's role in neuronal RNA processing and its interaction with pathology and cognitive resilience in AD, and suggest that maintenance of ZCCHC17 function may be a therapeutic strategy for preserving cognitive function in the setting of AD pathology.

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“…In an attempt to understand the functional significance of nucleolar CLU, the effect of CLU knockdown on ribogenesis was evaluated, which revealed negative association of CLU and rRNA synthesis. Other examples of tumour suppressor proteins like p14ARF and pNO40 have been shown to negatively regulate ribosome biogenesis by binding to UBF, a potent inducer of ribosome biosynthesis and reducing its occupancy at the rDNA promoter 36,37 . Another example is that of tumour suppressor MTG16a protein in breast cancer, which has been shown to inhibit ribogenesis by interacting with nucleolar remodelling complex (NoRC), which modifies the rDNA promoter chromatin by recruiting histone deacetylases to suppress rDNA transcription 38 .…”

Section: Discussionmentioning

confidence: 99%

Novel nucleolar localization of clusterin and its associated functions in human oral cancers: An in vitro and in silico analysis

Kadam

Harish

Dalvi

et al. 2020

Cell Biochemistry & Function

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Clusterin (CLU), a multifunctional chaperonic glycoprotein associated with diverse cellular functions has been shown to act as an oncogene or tumour suppressor gene in different cancers, implying a dual role in tumorigenesis. Here, we investigated the expression of CLU isoforms, their subcellular localization and functional significance in oral cancer cells. Significant downregulation of secretory CLU (sCLU) transcripts was observed in oral cancer cell lines and tumours versus normal cells while the nuclear CLU (nCLU) transcripts were undetectable. We demonstrated for the first time the nucleolar localization of sCLU, its response to different nucleolar stresses and association with cajal bodies post nucleolar stress. Functionally, knockdown of CLU revealed its negative association with ribosome biogenesis implying a possible tumour suppressor like role in oral cancers. Further, loss of sCLU in these cells also resulted in altered nuclear morphology and shrunken tubulin filaments. In addition, the levels of nucleolar Nucleophosmin 1(NPM1) and Fibrillarin, known to regulate nuclear morphology were downregulated indicating a possible role of sCLU in their stabilization. Further, an in silico docking approach to gain insights into the interaction of sCLU with nucleolar proteins NPM1, Fibrillarin, UBF and Nucleolin, revealed the involvement of a conserved region comprising of amino acid residues 140‐155 of sCLU β‐chain, specifically via the Phe152 residue in hydrophobic interactions with these client nucleolar proteins indicating a possible stabilizing or regulatory role of sCLU. Significance of the study This is the first study to demonstrate the nucleolar localization of sCLU and its associated functions in oral cancer cells. Downregulation of sCLU in oral cancer tissues and cell lines, and its negative association with ribogenesis suggest its tumour suppressor like role in oral cancers. The possible role of sCLU in stabilization or regulation of different nucleolar proteins thereby impacting their functions is also implicated.

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Ectopically expressed pNO40 suppresses ribosomal RNA synthesis by inhibiting UBF-dependent transcription activation

Cited by 7 publications

References 19 publications

Triptolide interrupts rRNA synthesis and induces the RPL23‑MDM2‑p53 pathway to repress lung cancer cells

Triptolide interrupts rRNA synthesis and induces the RPL23‑MDM2‑p53 pathway to repress lung cancer cells

ZCCHC17 modulates neuronal RNA splicing and supports cognitive resilience in Alzheimer’s disease

Novel nucleolar localization of clusterin and its associated functions in human oral cancers: An in vitro and in silico analysis

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