A Wiring of the Human Nucleolus

Hinsby, Anders M.; Kiemer, Lars; Karlberg, E. Olof; Lage, Kasper; Fausbøll, Anders; Juncker, Agnieszka Sierakowska; Andersen, Jens S.; Mann, Matthias; Brunak, Søren

doi:10.1016/j.molcel.2006.03.012

Cited by 57 publications

(52 citation statements)

References 56 publications

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“…To further investigate the interaction between these two proteins, we conducted immunofluorescent staining with HEK293 cells cotransfected with GFP-Ebp1 and HA-hBre1. As expected, GFP-p42 exclusively resided in the cytoplasm, whereas HA-hBre1 located in the nucleus, as indicated in previous reports (Andersen et al, 2005;Hinsby et al, 2006). By contrast, GFP-p48 distributed in both the cytoplasm and the nucleolus ( Figure 5C).…”

Section: Human Bre1 Interacts With Ebp1 and Inhibits Its Repressive Asupporting

confidence: 88%

Human BRE1 Is an E3 Ubiquitin Ligase for Ebp1 Tumor Suppressor

Liu¹,

Oh²,

Okada³

et al. 2009

MBoC

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Human Bre1, an E3 ligase for H2B monoubiquitination, binds p53 and enhances activator-dependent transcription. Ebp1, an ErbB3 receptor-binding protein, inhibits cell proliferation and acts as a tumor suppressor. Here, we show that hBre1 acts as an E3 ubiquitin ligase for Ebp1 tumor suppressor and promotes its polyubiquitination and degradation. Ebp1 is polyubiquitinated in cancer cells, which is regulated by its phosphorylation. We identified hBre1 acting as an E3 ligase for Ebp1 and increasing its polyubiquitination. Depletion of hBre1 blocks Ebp1's polyubiquitination and elevates its protein level, preventing cancer proliferation. hBre1 binds Ebp1 and suppresses its repressive effect on E2F-1. Moreover, Ebp1 protein level is substantially diminished in human cancers. It is robustly phosphorylated and localized in the nucleus of primary gliomas, correlating with hBre1 subcellular residency. Thus, hBre1 inhibits Ebp1's tumor suppressive activity through mediating its polyubiquitination and degradation. INTRODUCTIONIn yeast, histone H2B K123 monoubiquitination is regulated by the E3 ligase Bre1 and E2-conjugating enzyme RAD6 (Robzyk et al., 2000;Hwang et al., 2003;Wood et al., 2003a). This process is a prerequisite for the subsequent histone H3-K4 and K79 methylation (Sun and Allis, 2002;Wood et al., 2003b), which marks actively transcribed genes (SantosRosa et al., 2002). Additionally, PAF complex is also required for H2B ubiquitination (Ng et al., 2003;Wood et al., 2003b). In humans, the homologue of yeast Bre1 (RNF20), designated as hBre1, acts as an E3 ligase for H2B and promotes its ubiquitination at K120, the equivalent of yeast H2B K123 (Kim et al., 2005;Zhu et al., 2005). Moreover, it has a coactivator function in activator-dependent transcription of several genes. Interestingly, hBre1 directly binds p53 and is recruited to the MDM2 promoter, regulating p53-responsive gene transcription in a p53-dependent manner. Overexpression and depletion of hBre1 increases and decreases global H2B ubiquitination, respectively. By contrast, ectopic hRAD6A and hRAD6B, human homologues of yRAD6, do not affect H2B ubiquitination or H3 methylation, suggesting that hRAD6 proteins are not cognate E2 enzymes for hBre1 (Kim et al., 2005). In addition to transcriptional coactivation of specific genes (Osley, 2004), Bre1 in Drosophila is required for Notch signaling and histone modification (Bray et al., 2005).Ebp1 was originally identified as an ErbB3 receptor-binding protein , and it is the human homologue of a previously identified cell cycle-regulated mouse protein p38-2G4 (Radomski and Jost, 1995). PA2G4 gene encodes two Ebp1 isoforms, p48 and p42, which differentially regulate PC12 cell survival and differentiation Liu et al., 2006). P48 is 54 amino acids longer than p42 at its N terminus. The longer form p48 localizes in both the cytoplasm and the nucleolus and suppresses apoptosis, whereas the shorter form p42 predominantly resides in the cytoplasm and promotes cell differentiation . Ebp1 binds the ribosome and double-st...

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Section: Human Bre1 Interacts With Ebp1 and Inhibits Its Repressive Asupporting

confidence: 88%

Human BRE1 Is an E3 Ubiquitin Ligase for Ebp1 Tumor Suppressor

Liu¹,

Oh²,

Okada³

et al. 2009

MBoC

View full text Add to dashboard Cite

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“…Large and small mature ribosome particles are independently exported to the cytoplasm through an exportin 1 (CRM1) and Ran-GTP-dependent mechanism: export of 60S subunit requires the exchange of complexes Noc1-Noc2 by Noc3-Noc2 (102) and the association with the adaptor shuttling protein NMD3 (142), whereas the 40S needs the heterodimer Noc4p/Nop14p (103). The work by Hinsby et al exploited a machine learning-based predictor of nuclear export signals to analyze the late stage pre-40S complex, suggesting a role also for the human homolog of yeast DIM2p in the targeting and translocation of the late 40S to the cytoplasm (63).…”

Section: Structure Composition and Classical Functions Of The Nuclementioning

confidence: 99%

“…The nucleolome includes proteins related to cell cycle regulation, DNA damage and pre-mRNA processing (84), suggesting that this organelle may act as a multitasking district, being more than a simple ribosome factory (18,62,63,84,125). These particular multifunctional features are possibly related to the presence of many different nucleolar proteins endowed with multiple roles (e.g., NCL and Nopp140) (90a).…”

Section: Noncanonical Functions Of Dna Repair Proteins and Rna Metabomentioning

confidence: 99%

“…Nucleolar proteins unrelated to ribosome assembly mostly contain an RNA-binding motif or have a chaperone function and are able to shuttle between the nucleolus and the nucleoplasm (90a). It is currently known that nucleoli carry out many nonribosomal activities, such as: control of cell cycle and proliferation (62,63,130), stress sensing (18,21,64,96,108,124,139), tumor surveillance, DNA damage repair (18,41,84), regulation of protein stability and apoptosis, telomere metabolism (18), maturation of small RNAs, including tRNAs and small nuclear RNAs, maturation of the spliceosome and of the signal recognition particle (63,115,121), and also control of viral lifecycle (62,71), acting in several ways as a sequestration core facility ( Fig. 2) (21,40,63).…”

Section: Noncanonical Functions Of Dna Repair Proteins and Rna Metabomentioning

confidence: 99%

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Emerging Roles of the Nucleolus in Regulating the DNA Damage Response: The Noncanonical DNA Repair Enzyme APE1/Ref-1 as a Paradigmatical Example

Antoniali

Lirussi

Poletto

et al. 2014

Antioxidants & Redox Signaling

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Significance: An emerging concept in DNA repair mechanisms is the evidence that some key enzymes, besides their role in the maintenance of genome stability, display also unexpected noncanonical functions associated with RNA metabolism in specific subcellular districts (e.g., nucleoli). During the evolution of these key enzymes, the acquisition of unfolded domains significantly amplified the possibility to interact with different partners and substrates, possibly explaining their phylogenetic gain of functions. Recent Advances: After nucleolar stress or DNA damage, many DNA repair proteins can freely relocalize from nucleoli to the nucleoplasm. This process may represent a surveillance mechanism to monitor the synthesis and correct assembly of ribosomal units affecting cell cycle progression or inducing p53-mediated apoptosis or senescence. Critical Issues: A paradigm for this kind of regulation is represented by some enzymes of the DNA base excision repair (BER) pathway, such as apurinic/apyrimidinic endonuclease 1 (APE1). In this review, the role of the nucleolus and the noncanonical functions of the APE1 protein are discussed in light of their possible implications in human pathologies. Future Directions: A productive cross-talk between DNA repair enzymes and proteins involved in RNA metabolism seems reasonable as the nucleolus is emerging as a dynamic functional hub that coordinates cell growth arrest and DNA repair mechanisms. These findings will drive further analyses on other BER proteins and might imply that nucleic acid processing enzymes are more versatile than originally thought having evolved DNA-targeted functions after a previous life in the early RNA world. Antioxid. Redox Signal. 20, 621-639.

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“…Among those with annotations, more than 50% were annotated as nuclear proteins (Supplementary information, Figure S1B). Therefore, our fractionation could be considered as good quality nuclear fractionation [21,22].…”

Section: Quantitative Analysis Of Nuclei-associated Proteins Upon Tnfmentioning

confidence: 99%

Temporal and spatial profiling of nuclei-associated proteins upon TNF-α/NF-κB signaling

Wang

et al. 2009

Cell Res

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A Wiring of the Human Nucleolus

Cited by 57 publications

References 56 publications

Human BRE1 Is an E3 Ubiquitin Ligase for Ebp1 Tumor Suppressor

Human BRE1 Is an E3 Ubiquitin Ligase for Ebp1 Tumor Suppressor

Emerging Roles of the Nucleolus in Regulating the DNA Damage Response: The Noncanonical DNA Repair Enzyme APE1/Ref-1 as a Paradigmatical Example

Temporal and spatial profiling of nuclei-associated proteins upon TNF-α/NF-κB signaling

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