Ribosome biogenesis factors—from names to functions

Dörner, Kerstin; Ruggeri, Chiara; Zemp, Ivo; Kutay, Ulrike

doi:10.15252/embj.2022112699

Cited by 80 publications

(82 citation statements)

References 483 publications

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“…One could hypothesize that a HIF-dependent gene, such as a splicing factor, is directly or indirectly responsible for repressing the processing of RPS24S. Moreover, since many proteins of the small ribosomal subunit are involved in ribosome biogenesis (37), perhaps RPS24S is the favored isoform for this process and is repressed in hypoxia through energy stress-induced mTORC1 repression. Interestingly, even though mTORC1 inhibition induces autophagy, RPS24S repression through mTORC1 inhibition was not reversed upon the addition of Bafilomycin (Fig.…”

Section: Discussionmentioning

confidence: 99%

Autophagy-dependent alternative splicing event produces a more stable ribosomal protein S24 isoform that aids in hypoxic cell survival

Kerry,

Specker,

Mizzoni

et al. 2023

Preprint

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Overlapping or convergent stress-activated molecular pathways exist to coordinate cell fate in response to stimuli such as hypoxia, oxidative stress, DNA damage, and unfolded proteins. Cells can remodel the splicing and translation machineries to mount a specialized gene expression response to certain stresses. Here, we show that hypoxic human cells in 2D and 3D culture models increase the relative abundance by 1.7- to 2.6-fold and 4.7- to 11.5-fold, respectively, of a longer mRNA variant of ribosomal protein S24 (RPS24L) compared to a shorter mRNA variant (RPS24S) by favoring the inclusion of a 22 bp cassette exon. Mechanistically, RPS24L and RPS24S are induced and repressed, respectively, by distinct parallel pathways in hypoxia: RPS24L is induced in an autophagy-dependent manner, while RPS24S is reduced by mTORC1 repression and in a HIF-dependent manner. RPS24L is a more stable mRNA in hypoxia and produces a more stable protein isoform compared to RPS24S. Cells overexpressing RPS24L display improved survival and growth in hypoxia relative to control cells and cells overexpressing RPS24S, which display impaired survival. Previous work from our group showed a correlation between RPS24L levels and tumor hypoxia in prostate cancer. These data highlight RPS24L as a stress-induced alternative splicing event that favors hypoxic cell survival, which could be exploited by cancer cells in the tumor microenvironment.

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Section: Discussionmentioning

confidence: 99%

Autophagy-dependent alternative splicing event produces a more stable ribosomal protein S24 isoform that aids in hypoxic cell survival

Kerry,

Specker,

Mizzoni

et al. 2023

Preprint

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“…NOC1 in yeast works as a heterodimer with NOC2 during the initial transport and maturation of the ribosomal RNA (rRNA), a process that is completed by NOC2/NOC3 heterodimers (Milkereit et al, 2001). Furthermore, 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: 98%

“…NOC1 is a nucleolar protein that, together with NOC2 and NOC3, plays a critical role in the maturation of rRNA and the transport of the pre-ribosomal subunits (Sailer et al, 2022;Dorner et al, 2023). NOC1 in yeast works as a heterodimer with NOC2 during the initial transport and maturation of the ribosomal RNA (rRNA), a process that is completed by NOC2/NOC3 heterodimers (Milkereit et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

NOC1 is a Direct MYC Target, and Its Protein Interactome Dissects Its Activity in Controlling Nucleolar Function

Manara,

Radoani,

Belli

et al. 2023

Preprint

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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 the formation of abnormal structures formed by NOC1 within the nucleolus, outlining another aspect of NOC1 and MYC cooperation 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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“…Construction of this mega‐Dalton complex of rRNAs and ribosomal proteins is intricately coordinated by numerous additional factors. Recent advances and a comparison of ribosome assembly pathways across species will be highlighted in the review article on ribosome biogenesis factors by Ulrike Kutay and colleagues (Dörner et al , 2023).…”

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confidence: 99%