Germline NPM1 mutations lead to altered rRNA 2′-O-methylation and cause dyskeratosis congenita

Nachmani, Daphna; Bothmer, Anne; Grisendi, Silvia; Mele, Aldo; Bothmer, Dietmar; Lee, Jonathan D.; Monteleone, Emanuele; Cheng, Ke; Zhang, Yang; Bester, Assaf C.; Guzzetti, Alison; Mitchell, Caitlin; Mendez, Lourdes M.; Pozdnyakova, Olga; Sportoletti, Paolo; Martelli, Maria Paola; Vulliamy, Tom; Safra, Modi; Schwartz, Schraga; Luzzatto, Lucio; Bluteau, Olivier; Soulier, Jean; Darnell, Robert B.; Falini, Brunangelo; Dokal, Inderjeet; Ito, Keisuke; Clohessy, John G.; Pandolfi, Pier Paolo

doi:10.1038/s41588-019-0502-z

Cited by 94 publications

(88 citation statements)

References 77 publications

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“…A landmark paper recently and convincingly established that NPM1 is a key mediator of rRNA post-transcriptional modifications in mouse embryonic fibroblasts (MEFs) and HSCs [95]. Nachmani and colleagues [95] demonstrated that NPM1 is associated with a large number of box H/ACA and box C/D snoRNAs, and that the 2'O-Me levels of five 28S rRNA sites are specifically and significantly impaired in Npm1 −/− MEFs, yet no changes in Ψ were detected. NPM1 directly interacts with FBL to promote the correct assembly of box C/D snoRNAs into snoRNPs.…”

Section: Regulation Of Rrna Modificationsmentioning

confidence: 99%

Ribosome and Translational Control in Stem Cells

Gabut

Bourdelais

Durand

2020

Cells

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Embryonic stem cells (ESCs) and adult stem cells (ASCs) possess the remarkable capacity to self-renew while remaining poised to differentiate into multiple progenies in the context of a rapidly developing embryo or in steady-state tissues, respectively. This ability is controlled by complex genetic programs, which are dynamically orchestrated at different steps of gene expression, including chromatin remodeling, mRNA transcription, processing, and stability. In addition to maintaining stem cell homeostasis, these molecular processes need to be rapidly rewired to coordinate complex physiological modifications required to redirect cell fate in response to environmental clues, such as differentiation signals or tissue injuries. Although chromatin remodeling and mRNA expression have been extensively studied in stem cells, accumulating evidence suggests that stem cell transcriptomes and proteomes are poorly correlated and that stem cell properties require finely tuned protein synthesis. In addition, many studies have shown that the biogenesis of the translation machinery, the ribosome, is decisive for sustaining ESC and ASC properties. Therefore, these observations emphasize the importance of translational control in stem cell homeostasis and fate decisions. In this review, we will provide the most recent literature describing how ribosome biogenesis and translational control regulate stem cell functions and are crucial for accommodating proteome remodeling in response to changes in stem cell fate.

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Section: Regulation Of Rrna Modificationsmentioning

confidence: 99%

Ribosome and Translational Control in Stem Cells

Gabut

Bourdelais

Durand

2020

Cells

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“…This is in line with the unexpected 2′-O-methylation alteration observed in X-DC. Very recently, a study linked the rRNA 2′-O-methylation alteration caused by NPM1 mutations to the development of congenital dyskeratosis [116]. These results demonstrate the complex etiology of such diseases and how a common phenotype can arise as the result of different alterations.…”

Section: Discussionmentioning

confidence: 90%

Disruption of the RNA modifications that target the ribosome translation machinery in human cancer

2020

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Genetic and epigenetic changes deregulate RNA and protein expression in cancer cells. In this regard, tumors exhibit an abnormal proteome in comparison to the corresponding normal tissues. Translation control is a crucial step in the regulation of gene expression regulation under normal and pathological conditions that ultimately determines cellular fate. In this context, evidence shows that transfer and ribosomal RNA (tRNA and rRNA) modifications affect the efficacy and fidelity of translation. The number of RNA modifications increases with the complexity of organisms, suggesting an evolutionary diversification of the possibilities for fine-tuning the functions of coding and non-coding RNAs. In this review, we focus on alterations of modifications of transfer and ribosomal RNA that affect translation in human cancer. This variation in the RNA modification status can be the result of altered modifier expression (writers, readers or erasers), but also due to components of the machineries (C/D or H/ ACA boxes) or alterations of proteins involved in modifier expression. Broadening our understanding of the mechanisms by which site-specific modifications modulate ribosome activity in the context of tumorigenesis will enable us to enrich our knowledge about how ribosomes can influence cell fate and form the basis of new therapeutic opportunities.

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“…Zhou et al, 2017). For instance, germline NPM1 mutations impair the binding capacity of FBL to snoRNAs, which alters rRNA 2 0 -O-methylation and causes dyskeratosis congenita (Nachmani et al, 2019). The internal 2 0 -O-methylation in snRNAs appears to be guided by scaRNAs and is essential for small nuclear RNP (snRNP) formation and splicing in mammals (Izumikawa et al, 2019;Meier, 2017;Yu, Shu, & Steitz, 1998).…”

Section: Snorna Guide-based Rna-protein Interactionsmentioning

confidence: 99%

Classification and function of RNA–protein interactions

Liu

Liang

et al. 2020

WIREs RNA

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Almost all RNAs need to interact with proteins to fully exert their functions, and proteins also bind to RNAs to act as regulators. It has now become clear that RNA-protein interactions play important roles in many biological processes among organisms. Despite the great progress that has been made in the field, there is still no precise classification system for RNA-protein interactions, which makes it challenging to further decipher the functions and mechanisms of these interactions. In this review, we propose four different categories of RNA-protein interactions according to their basic characteristics: RNA motif-dependent RNA-protein interactions, RNA structure-dependent RNA-protein interactions, RNA modification-dependent RNA-protein interactions, and RNA guide-based RNA-protein interactions. Moreover, the integration of different types of RNA-protein interactions and the regulatory factors implicated in these interactions are discussed. Furthermore, we emphasize the functional diversity of these four types of interactions in biological processes and disease development and assess emerging trends in this exciting research field.

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Germline NPM1 mutations lead to altered rRNA 2′-O-methylation and cause dyskeratosis congenita

Cited by 94 publications

References 77 publications

Ribosome and Translational Control in Stem Cells

Ribosome and Translational Control in Stem Cells

Disruption of the RNA modifications that target the ribosome translation machinery in human cancer

Classification and function of RNA–protein interactions

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