Treacle Sticks the Nucleolar Responses to DNA Damage Together

Gál, Zita; Nieto, Blanca; Boukoura, Stavroula; Rasmussen, Anna Vestergaard; Larsen, Dorthe Helena

doi:10.3389/fcell.2022.892006

Cited by 14 publications

(14 citation statements)

References 114 publications

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“…For instance, BBS has been shown to regulate neural crest migration which involves EMT and delamination of neuroepithelial cells [31]. An analogous situation has been described in Treacher-Collins and Miller syndromes where mutations affecting the ubiquitous processes of ribosome biogenesis and pyrimidine biosynthesis cause very specific neurocristopathic clinical features [32–35].…”

Section: Discussionmentioning

confidence: 99%

De-suppression of mesenchymal cell identities and variable phenotypic outcomes associated with knockout ofBbs1

Freke,

Martins,

Davies

et al. 2023

Preprint

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Bardet-Biedl syndrome (BBS) is an archetypal ciliopathy caused by dysfunction of primary cilia. BBS affects multiple tissues, including the kidney, eye and hypothalamic satiety response. Understanding pan-tissue mechanisms of pathogenesis versus those which are tissue specific, and gauging their associated inter-individual variation owing to genetic background and stochastic processes, is of paramount importance in syndromology. The BBSome is a membrane trafficking and intraflagellar transport (IFT) adaptor protein complex formed by 8 BBS proteins, including BBS1, which is the most commonly mutated gene in BBS. To investigate disease pathogenesis we generated a series of clonal renal collecting duct IMCD3 cell lines carrying defined biallelic nonsense or frameshift mutations inBbs1, as well as a panel of matching wild-type CRISPR control clones. Using a phenotypic screen and an unbiased multi-omics approach we note significant clonal variability for all assays, emphasising the importance of analysing panels of genetically-defined clones. Our results suggest that BBS1 is required for suppression of mesenchymal cell identities as IMCD3 cell passage number increases. This was associated with a failure to express epithelial cell markers and tight junction formation, which was variable amongst clones. Transcriptomic analysis of hypothalamic preparations from BBS mutant mice, and BBS patient fibroblasts, suggested that dysregulation of epithelial-to-mesenchymal transition (EMT) genes is a general predisposing feature of BBS across tissues. Collectively this work suggests that the dynamic stability of the BBSome is essential for suppression of mesenchymal cell identities as epithelial cells differentiate.

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Section: Discussionmentioning

confidence: 99%

De-suppression of mesenchymal cell identities and variable phenotypic outcomes associated with knockout ofBbs1

Freke,

Martins,

Davies

et al. 2023

Preprint

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“…Mutations of genes related to the Pol I transcription complex (such as treacle ribosome biogenesis factor‐1 [ TCOF1 ]) cause TCS because the ensuing decreased transcription/processing of rRNA activates p53. 41 Mice or African clawed frogs lacking TCOF1 function show TCS‐like phenotypes, including skull dysplasia. 41 In contrast, BCS is caused by mutation of the EMG N1‐specific pseudouridine methyltransferase ( EMG1 ) gene.…”

Section: Nucleolar Stress and Human Ribosomal Diseasesmentioning

confidence: 99%

“… 41 Mice or African clawed frogs lacking TCOF1 function show TCS‐like phenotypes, including skull dysplasia. 41 In contrast, BCS is caused by mutation of the EMG N1‐specific pseudouridine methyltransferase ( EMG1 ) gene. EMG1 is degraded, which impairs pseudouridine rRNA modification and processing, and results in microcephaly.…”

Section: Nucleolar Stress and Human Ribosomal Diseasesmentioning

confidence: 99%

Nucleolar stress: Molecular mechanisms and related human diseases

et al. 2023

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Ribosome biogenesis in the nucleolus is an important process that consumes 80% of a cell's intracellular energy supply. Disruption of this process results in nucleolar stress, triggering the activation of molecular systems that respond to this stress to maintain homeostasis. Although nucleolar stress was originally thought to be caused solely by abnormalities of ribosomal RNA (rRNA) and ribosomal proteins (RPs), an accumulating body of more current evidence suggests that many other factors, including the DNA damage response and oncogenic stress, are also involved in nucleolar stress response signaling. Cells reacting to nucleolar stress undergo cell cycle arrest or programmed death, mainly driven by activation of the tumor suppressor p53. This observation has nominated nucleolar stress as a promising target for cancer therapy. However, paradoxically, some RP mutations have also been implicated in cancer initiation and progression, necessitating caution. In this article, we summarize recent findings on the molecular mechanisms of nucleolar stress and the human ribosomal diseases and cancers that arise in its wake.

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“…This transformation process exhibits similarities to the fusion of liquid droplets. Treacle is the main molecule present in the FC, and it has both transcription-dependent and - independent functions (Gal et al, 2022). Its role in ribosome biogenesis is well-documented since it assists in the transcription and processing of rRNA (Gonzales et al, 2005; Lin & Yeh, 2009; Valdez et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Treacle’s ability to form liquid phase condensates is essential for nucleolar fibrillar center assembly, efficient rRNA transcription and processing, and rRNA gene repair

Velichko,

Kovina,

Luzhin

et al. 2023

Preprint

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It is known that major nuclear processes occur differently in the nucleolus when compared to the remainder of the nucleus. This variation could be associated with the nature of the nucleolus, which is considered a multicomponent liquid environment. Among the numerous nucleolar proteins, Treacle holds a special place due to a wealth of experimental evidence highlighting its significance for transcription as well as DNA repair in the nucleolus. However, it remains unclear how Treacle exerts its multifaceted influence on nucleolar processes from a mechanistic perspective. In this study, we demonstrate that Treacle can undergo phase separation in living cells and characterize in detail the structural basis of its condensation and generation of cooperative Treacle-TOPBP1 liquid assemblies. Our data clearly show that the phase separation of Treacle serves a key role in ribosomal DNA transcription and DNA repair. In these processes, Treacle biomolecular condensates serve as a platform for attracting and retaining transcription machinery (UBF1, Pol I) or repair factors (TOPBP1, ATR, and others) on ribosomal genes. Moreover, Treacle and TOPBP1 can form cooperative nuclear biomolecular condensates in the absence of DNA damage. These damage-independent Treacle-TOPBP1 liquid droplets act as fully functional molecular platforms for DNA damage response activation. Our data indicate that by forming biomolecular condensates, Treacle can facilitate intracellular processes and target them to the required intranuclear locations.

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Treacle Sticks the Nucleolar Responses to DNA Damage Together

Cited by 14 publications

References 114 publications

De-suppression of mesenchymal cell identities and variable phenotypic outcomes associated with knockout ofBbs1

De-suppression of mesenchymal cell identities and variable phenotypic outcomes associated with knockout ofBbs1

Nucleolar stress: Molecular mechanisms and related human diseases

Treacle’s ability to form liquid phase condensates is essential for nucleolar fibrillar center assembly, efficient rRNA transcription and processing, and rRNA gene repair

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