The novel role of hnRNP UL1 in human cell nucleoli
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE202821 | GEO | 2022/08/25
REPOSITORIES: GEO
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Project description:hnRNP UL1 plays an important function in cell nuclei, where it is recruited to DNA damage sites and is involved in the repair of DNA double strand breaks. Furthermore, this protein is known as a transcriptional repressor of RNA polymerase II genes. In the present study, we have shown that hnRNP UL1 is also localized in the nucleoli. Revealing its function, we figured out that hnRNP UL1 stimulates rDNA gene transcription and may be involved in the transport of the proteins between the nucleolus and the nucleoplasm. Moreover, we observed that cells with hnRNP UL1 silencing are more sensitive to DNA damage, suggesting its role in rDNA repair pathways and nucleolar genome integrity. Indeed, we confirmed that hnRNP UL1 interacts with yH2A.X, RPA32, XRCC1, and Chk1 in cell nucleoli, suggesting its involvement in repairing of DNA damages.
2022-10-15 | PXD033233 | Pride
Project description:We performed ChIP-seq with antibody targeting hnRNP UL1 at 0, 4h and 10h following LPS stimulation in RAW 264.7 cells. NGS and data analysis were done by Novogen China Co. Ltd. We found that hnRNP UL1 binds to chromatin DNA broadly and dynamically during inflammatory response. hnRNP UL1 binds to genes' promoter mainly. And NF-κB binding sites (κB sites) were significantly enriched in the motifs bound by hnRNP UL1.
2022-06-01 | GSE196201 | GEO
Project description:The novel role of hnRNP UL1 in human cell nucleoli
| PRJNA837419 | ENA
Project description:Induction of DNA double-strand breaks (DSBs) in ribosomal DNA (rDNA) repeats is associated with ATM-dependent repression of ribosomal RNA synthesis and large-scale reorganization of nucleolar architecture, but the signaling events that regulate these responses are largely elusive. Here we show that the nucleolar response to rDNA breaks is dependent on both ATM and ATR activity. We further demonstrate that ATM- and NBS1-dependent recruitment of TOPBP1 in the nucleoli is required for inhibition of ribosomal RNA synthesis and nucleolar segregation in response to rDNA breaks. Mechanistically, TOPBP1 recruitment is mediated by phosphorylation-dependent interactions between three of its BRCT domains and conserved phosphorylated Ser/Thr residues at the C-terminus of the nucleolar phosphoprotein Treacle. Our data thus reveal an important cooperation between TOPBP1 and Treacle in the signaling cascade that triggers transcriptional inhibition and nucleolar segregation in response to rDNA breaks.
2019-12-06 | PXD015138 | Pride
Project description:Nucleolar ribosomal DNA (rDNA) repeats control ribosome manufacturing. rDNA harbors a ribosomal RNA (rRNA) gene and an intergenic spacer (IGS). RNA polymerase (Pol) I transcribes rRNA genes yielding the rRNA components of ribosomes. Pol II at the IGS induces rRNA production by preventing Pol I from excessively synthesizing IGS non-coding RNAs (ncRNAs) that can disrupt nucleoli. At the IGS, Pol II regulatory processes and whether Pol I function can be beneficial remain unknown. Here, we identify IGS Pol II regulators, uncovering nucleolar optimization via IGS Pol I. Compartment-enriched proximity-dependent biotin identification (compBioID) showed enrichment of the TATA-less promoter-binding TBPL1 and transcription regulator PAF1 with IGS Pol II. TBPL1 localizes to TCT motifs, driving Pol II and Pol I and maintaining its baseline ncRNA levels. PAF1 promotes Pol II elongation, preventing unscheduled R-loops that hyper-restrain IGS Pol I and its ncRNAs. PAF1 or TBPL1 deficiency disrupts nucleolar organization and rRNA biogenesis. In PAF1-deficient cells, repressing unscheduled IGS R-loops rescues nucleolar organization and rRNA production. Depleting IGS Pol I-dependent ncRNAs is sufficient to compromise nucleoli. We present the interactome of nucleolar Pol II and show its control by TBPL1 and PAF1 ensures IGS Pol I ncRNAs maintaining nucleolar structure and operation.
2024-10-09 | GSE261857 | GEO
Project description:The nucleolus is a membraneless organelle responsible for ribosome biogenesis, perinuclear heterochromatin formation, and genome stability regulation. However, how cell fate decision occurs, including early embryonic development, ESC differentiation, and tumorigenesis, remains poorly understood at the nucleolar level. It has been observed that large nucleoli and rDNA hyperactivity are common in pluripotent stem cells and tumor cells, while the nucleolus shrinks and rDNA transcriptional activity decrease during lineage commitment. iPSCs nucleolar size and rDNA transcriptional activity are greater than that before reprogramming. It remains unclear how and when the differentiated cell nucleoli convert to the stem cell nucleoli during iPSC reprogramming.In this study, we found that nucleolar remodeling, manifested as enlarged nucleolus, activation of rDNA transcription, enhanced activity of nucleolar organizing regions (NORs), and conversion of reticular nucleolar ultrastructure into low-granular, is an early and stage-specific event that occurs during iPSCs reprogramming. Our study highlights the importance of rDNA transcriptional activity in the early stages of iPSC reprogramming, which is crucial for nucleolar remodeling and regaining stemness. Interfering rDNA transcription hinders nucleolar remodeling, which has disastrous consequences for chromatin remodeling in early stage of iPSC reprogramming and iPSCs establishment. Moreover, our results revealed a nucleolar regulation on chromatin accessibility during iPSC reprogramming and identified some candidate genes (Mybl2, Bard1 and other chromosome related genes) that might be associated with iPSC reprogramming, which may apply to nucleolar remodeling in other cell fated decision.
2024-10-01 | GSE232871 | GEO
Project description:The nucleolus is a membraneless organelle responsible for ribosome biogenesis, perinuclear heterochromatin formation, and genome stability regulation. However, how cell fate decision occurs, including early embryonic development, ESC differentiation, and tumorigenesis, remains poorly understood at the nucleolar level. It has been observed that large nucleoli and rDNA hyperactivity are common in pluripotent stem cells and tumor cells, while the nucleolus shrinks and rDNA transcriptional activity decrease during lineage commitment. iPSCs nucleolar size and rDNA transcriptional activity are greater than that before reprogramming. It remains unclear how and when the differentiated cell nucleoli convert to the stem cell nucleoli during iPSC reprogramming.In this study, we found that nucleolar remodeling, manifested as enlarged nucleolus, activation of rDNA transcription, enhanced activity of nucleolar organizing regions (NORs), and conversion of reticular nucleolar ultrastructure into low-granular, is an early and stage-specific event that occurs during iPSCs reprogramming. Our study highlights the importance of rDNA transcriptional activity in the early stages of iPSC reprogramming, which is crucial for nucleolar remodeling and regaining stemness. Interfering rDNA transcription hinders nucleolar remodeling, which has disastrous consequences for chromatin remodeling in early stage of iPSC reprogramming and iPSCs establishment. Moreover, our results revealed a nucleolar regulation on chromatin accessibility during iPSC reprogramming and identified some candidate genes (Mybl2, Bard1 and other chromosome related genes) that might be associated with iPSC reprogramming, which may apply to nucleolar remodeling in other cell fated decision.
2024-10-01 | GSE232870 | GEO
Project description:Ribosomal DNA (rDNA) arrays are highly repetitive regions of the genome which encode essential genes required to produce ribosomes. DNA double-stranded breaks (DSBs) generated within rDNA genes elicit a unique cellular response involving robust transcriptional silencing and nucleolar reorganization into ‘cap’ structures at the nucleolar periphery. This process is coordinated by the nucleolar scaffolding protein TCOF1, which functions to recruit the DNA repair proteins NBS1 and TOPBP1 that activate the ATM and ATR kinases, resulting in ribosomal RNA (rRNA) transcriptional silencing and nucleolar segregation. However, the DNA damage and repair response at rDNA arrays remains incompletely understood. Here, we investigate the cellular response to rDNA DSBs using proteomics and genetic CRISPR-Cas9 screening. We show that the protein UFMylation pathway and the HUSH complex are important for cell viability and survival in response to rDNA DSBs, and that the E3 UFM1-ligase UFL1 and its heterodimer DDRGK1 are associated with TCOF1 at nucleolar caps. Loss of UFL1 leads to impaired ATM activation, reduced rRNA transcriptional silencing, and an overall reduction in nucleolar segregation. We identified ATM, UNC45A and SMC6 as UFMylated proteins, in which UFMylation may facilitate ATM activation and segregation of damaged rDNA to the nucleolar periphery. Altogether, our findings provide the first evidence for a role for UFMylation in rDNA DSB repair.
2024-01-29 | GSE253809 | GEO
Project description:Ribosomal DNA (rDNA) arrays are highly repetitive regions of the genome which encode essential genes required to produce ribosomes. DNA double-stranded breaks (DSBs) generated within rDNA genes elicit a unique cellular response involving robust transcriptional silencing and nucleolar reorganization into ‘cap’ structures at the nucleolar periphery. This process is coordinated by the nucleolar scaffolding protein TCOF1, which functions to recruit the DNA repair proteins NBS1 and TOPBP1 that activate the ATM and ATR kinases, resulting in ribosomal RNA (rRNA) transcriptional silencing and nucleolar segregation. However, the DNA damage and repair response at rDNA arrays remains incompletely understood. Here, we investigate the cellular response to rDNA DSBs using proteomics and genetic CRISPR-Cas9 screening. We show that the protein UFMylation pathway and the HUSH complex are important for cell viability and survival in response to rDNA DSBs, and that the E3 UFM1-ligase UFL1 and its heterodimer DDRGK1 are associated with TCOF1 at nucleolar caps. Loss of UFL1 leads to impaired ATM activation, reduced rRNA transcriptional silencing, and an overall reduction in nucleolar segregation. We identified ATM, UNC45A and SMC6 as UFMylated proteins, in which UFMylation may facilitate ATM activation and segregation of damaged rDNA to the nucleolar periphery. Altogether, our findings provide the first evidence for a role for UFMylation in rDNA DSB repair.
2024-09-16 | PXD048568 | Pride
Project description:PARP inhibitors (PARPi) prevent cancer cell growth by inducing synthetic lethality with DNA repair defects (e.g., in BRCA1/2 mutant cells). We have identified an alternate pathway for PARPi-mediated growth control in BRCA1/2-intact breast cancer cells involving rDNA transcription and ribosome biogenesis. PARP-1 binds to snoRNAs, which stimulate PARP-1 catalytic activity in the nucleolus independent of DNA damage. Activated PARP-1 ADP-ribosylates DDX21, an RNA helicase that localizes to nucleoli and promotes rDNA transcription when ADP-ribosylated. Treatment with PARPi or mutation of the ADP-ribosylation sites reduce DDX21 nucleolar localization, rDNA transcription, ribosome biogenesis, protein translation, and cell growth. The salient features of this pathway are evident in xenografts in mice and human breast cancer patient samples. Elevated levels of PARP-1 and nucleolar DDX21 are associated with cancer-related outcomes. Our studies provide a mechanistic rationale for efficacy of PARPi in cancer cells lacking defects in DNA repair whose growth is inhibited by PARPi.
2019-07-31 | GSE115760 | GEO