A co-transcriptional ribosome assembly checkpoint controls nascent large ribosomal subunit maturation

Sanghai, Zahra Assur; Piwowarczyk, Rafał; Broeck, Arnaud Vanden; Klinge, Sebastian

doi:10.1038/s41594-023-00947-3

Cited by 15 publications

(6 citation statements)

References 42 publications

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“…DEAD-box DNA/RNA helicases such as DDX21 have been implicated in the removal of aberrant R-loops (DNA/RNA hybrids) during RNA transcription [97][98][99] , but Plasmodium DDX21 has also been implicated with rRNA maturation in ribosome biogenesis 37 . Other RNA-binding proteins that copurified with PfHO, Nop52 and RAP, also show low-level sequence homology to ribosome assembly factors 100,101 . Prokaryotic ribosome assembly is a co-transcriptional process regulated by, and in close proximity to RNA transcriptional machinery [102][103][104] .…”

Section: Discussionmentioning

confidence: 99%

Malaria parasites require a divergent heme oxygenase for apicoplast gene expression and biogenesis

Blackwell,

Jami-Alahmadi,

Nasamu

et al. 2024

Preprint

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Malaria parasites have evolved unusual metabolic adaptations that specialize them for growth within heme-rich human erythrocytes. During blood-stage infection,Plasmodium falciparumparasites internalize and digest abundant host hemoglobin within the digestive vacuole. This massive catabolic process generates copious free heme, most of which is biomineralized into inert hemozoin. Parasites also express a divergent heme oxygenase (HO)-like protein (PfHO) that lacks key active-site residues and has lost canonical HO activity. The cellular role of this unusual protein that underpins its retention by parasites has been unknown. To unravel PfHO function, we first determined a 2.8 Å-resolution X-ray structure that revealed a highly α-helical fold indicative of distant HO homology. Localization studies unveiled PfHO targeting to the apicoplast organelle, where it is imported and undergoes N-terminal processing but retains most of the electropositive transit peptide. We observed that conditional knockdown of PfHO was lethal to parasites, which died from defective apicoplast biogenesis and impaired isoprenoid-precursor synthesis. Complementation and molecular-interaction studies revealed an essential role for the electropositive N-terminus of PfHO, which selectively associates with the apicoplast genome and enzymes involved in nucleic acid metabolism and gene expression. PfHO knockdown resulted in a specific deficiency in levels of apicoplast-encoded RNA but not DNA. These studies reveal an essential function for PfHO in apicoplast maintenance and suggest thatPlasmodiumrepurposed the conserved HO scaffold from its canonical heme-degrading function in the ancestral chloroplast to fulfill a critical adaptive role in organelle gene expression.

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Section: Discussionmentioning

confidence: 99%

Malaria parasites require a divergent heme oxygenase for apicoplast gene expression and biogenesis

Blackwell,

Jami-Alahmadi,

Nasamu

et al. 2024

Preprint

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“…The maturation of the 47S pre-rRNA is co-transcriptional and is initiated as soon as the transcript emerges from the Pol I complex by the assembly of ribosome biogenesis factors and ribosomal proteins into a premature ribosomal particle in the nucleolus ( 12 , 98 , 99 ). The earliest stable pre-ribosomal intermediate to form is called the 90S pre-ribosome or small subunit processome (SSU), which comprises >70 assembly factors, including the transcription U three proteins (t-UTPs), the U3 small nucleolar ribonucleoprotein (U3 snoRNP), several small subunit ribosomal proteins and the nascent pre-rRNA transcript.…”

Section: Aberrant Rrna Processing In Cancermentioning

confidence: 99%

“…While this review primarily focuses into the mechanisms and consequences of increased ribosome biogenesis in cancer, the intertwining regulatory mechanisms of ribosome biogenesis and heterogeneity raise questions about their interplay and significance in cancer progression. Given that most rRNA processing and modifications occur concomitantly with transcription, the factors involved likely exhibit tight spatial and temporal coordination with RNA Pol I elongation ( 12 , 98 , 99 ). This implies that changes in RNA Pol I transcription rate could result in alteration in rRNA modification pattern.…”

Section: Future Perspective and Conclusionmentioning

confidence: 99%

The impact of ribosome biogenesis in cancer: from proliferation to metastasis

Hwang,

Denicourt

2024

NAR Cancer

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The dysregulation of ribosome biogenesis is a hallmark of cancer, facilitating the adaptation to altered translational demands essential for various aspects of tumor progression. This review explores the intricate interplay between ribosome biogenesis and cancer development, highlighting dynamic regulation orchestrated by key oncogenic signaling pathways. Recent studies reveal the multifaceted roles of ribosomes, extending beyond protein factories to include regulatory functions in mRNA translation. Dysregulated ribosome biogenesis not only hampers precise control of global protein production and proliferation but also influences processes such as the maintenance of stem cell-like properties and epithelial-mesenchymal transition, contributing to cancer progression. Interference with ribosome biogenesis, notably through RNA Pol I inhibition, elicits a stress response marked by nucleolar integrity loss, and subsequent G1-cell cycle arrest or cell death. These findings suggest that cancer cells may rely on heightened RNA Pol I transcription, rendering ribosomal RNA synthesis a potential therapeutic vulnerability. The review further explores targeting ribosome biogenesis vulnerabilities as a promising strategy to disrupt global ribosome production, presenting therapeutic opportunities for cancer treatment.

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“…NOC1 in yeast works as a heterodimer with NOC2 during the initial maturation of the ribosomal RNA (rRNA) and in the transport of the pre-60S ribosomal subunit, a process that is completed by NOC2/NOC3 heterodimers ( Milkereit et al, 2001 ). Studies on the distribution of affinity-tagged NOC1 and, more recently, proteomics and crosslinking coupled to mass spectrometry, confirmed the presence of NOC1 in the early pre-60S complex ( Sailer et al, 2022 ; Dorner et al, 2023 ), while cryo-EM studies showed its role in the formation of heterodimers with NOC2, essential for the quality-control checkpoint of the maturation of the large ribosome subunit ( Sanghai et al, 2023 ).…”

Section: Introductionmentioning

confidence: 96%

NOC1 is a direct MYC target, and its protein interactome dissects its activity in controlling nucleolar function

Manara,

Radoani,

Belli

et al. 2023

Front. Cell Dev. Biol.

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The nucleolus is a subnuclear compartment critical in ribosome biogenesis and cellular stress responses. These mechanisms are governed by a complex interplay of proteins, including NOC1, a member of the NOC family of nucleolar proteins responsible for controlling rRNA processing and ribosomal maturation. This study reveals a novel relationship between NOC1 and MYC transcription factor, known for its crucial role in controlling ribosomal biogenesis, cell growth, and proliferation. Here, we demonstrate that NOC1 functions as a direct target of MYC, as it is transcriptionally induced through a functional MYC-binding E-box sequence in the NOC1 promoter region. Furthermore, protein interactome analysis reveals that NOC1-complex includes the nucleolar proteins NOC2 and NOC3 and other nucleolar components such as Nucleostemin1 Ns1 transporters of ribosomal subunits and components involved in rRNA processing and maturation. In response to MYC, NOC1 expression and localization within the nucleolus significantly increase, suggesting a direct functional link between MYC activity and NOC1 function. Notably, NOC1 over-expression leads to the formation of large nuclear granules and enlarged nucleoli, which co-localize with nucleolar fibrillarin and Ns1. Additionally, we demonstrate that NOC1 expression is necessary for Ns1 nucleolar localization, suggesting a role for NOC1 in maintaining nucleolar structure. Finally, the co-expression of NOC1 and MYC enhances nucleolus size and maintains their co-localization, outlining another aspect of the cooperation between NOC1 and MYC in nucleolar dynamics. This study also reveals an enrichment with NOC1 with few proteins involved in RNA processing, modification, and splicing. Moreover, proteins such as Ythdc1, Flacc, and splenito are known to mediate N6-methyladenosine (m6A) methylation of mRNAs in nuclear export, revealing NOC1’s potential involvement in coordinating RNA splicing and nuclear mRNA export. In summary, we uncovered novel roles for NOC1 in nucleolar homeostasis and established its direct connection with MYC in the network governing nucleolar structure and function. These findings also highlight NOC1’s interaction with proteins relevant to specific RNA functions, suggesting a broader role in addition to its control of nucleolar homeostasis and providing new insight that can be further investigated.

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A co-transcriptional ribosome assembly checkpoint controls nascent large ribosomal subunit maturation

Cited by 15 publications

References 42 publications

Malaria parasites require a divergent heme oxygenase for apicoplast gene expression and biogenesis

Malaria parasites require a divergent heme oxygenase for apicoplast gene expression and biogenesis

The impact of ribosome biogenesis in cancer: from proliferation to metastasis

NOC1 is a direct MYC target, and its protein interactome dissects its activity in controlling nucleolar function

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