The human 18S rRNA base methyltransferases DIMT1L and WBSCR22-TRMT112 but not rRNA modification are required for ribosome biogenesis

Zorbas, Christiane; Nicolas, Emilien; Wacheul, Ludivine; Huvelle, Emmeline; Heurgué-Hamard, Valérie; Lafontaine, Denis L. J.

doi:10.1091/mbc.e15-02-0073

Cited by 130 publications

(195 citation statements)

References 60 publications

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“…As an 18S rRNA base methyltransferase, DIMT1 was previously found to regulate ribosomal proteins . Our results strongly suggest that it is an upstream regulator of IRF4 /IRF4 translation.…”

Section: Discussionsupporting

confidence: 68%

“…Although we could not determine the exact mechanism of DIMT1 in myeloma pathogenesis, regulators of ribosomal proteins have been found to play crucial roles in carcinogenesis. For instance, WBSCR22, another 18S rRNA base methyltransferase, was found to be associated with metastasis/invasion in solid tumors and promoting survival in myeloma cells . In addition, alteration of ribosomal proteins, such as RPS14 and RPL22, have been detected in cases of hematological malignancies .…”

Section: Discussionmentioning

confidence: 99%

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Hypoxia‐inducible microRNA‐210 regulates the DIMT1‐IRF4 oncogenic axis in multiple myeloma

et al. 2017

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Multiple myeloma (MM) is characterized by the accumulation of a population of malignant plasma cells within the bone marrow and its microenvironment. A hypoxic niche is located within the microenvironment, which causes myeloma cells to become quiescent, anti‐apoptotic, glycolytic, and immature. Cell heterogeneity may be related to distinct gene expression profiles under hypoxic and normoxic conditions. During hypoxia, myeloma cells acquire these phenotypes by downregulating interferon regulatory factor 4 (IRF4), an essential transcription factor in myeloma oncogenesis. To identify essential microRNAs and their targets regulated under hypoxic conditions, we undertook microRNA and cDNA microarray analyses using hypoxia‐exposed primary MM samples and myeloma cell lines. Under hypoxia, only miR‐210 was highly upregulated and was accompanied by direct downregulation of an 18S rRNA base methyltransferase, DIMT1. This inverse expression correlation was validated by quantitative RT‐PCR for primary MM samples. We further determined that DIMT1 has an oncogenic potential as its knockdown reduced tumorigenicity of myeloma cells through regulation of IRF4 expression. Notably, by analyzing gene expression omnibus datasets in the National Center for Biotechnology Information database, we found that DIMT1 expression increased gradually with MM progression. In summary, by screening for targets of hypoxia‐inducible microRNA‐210, we identified DIMT1 as a novel diagnostic marker and therapeutic target for all molecular subtypes of MM.

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“…As an 18S rRNA base methyltransferase, DIMT1 was previously found to regulate ribosomal proteins . Our results strongly suggest that it is an upstream regulator of IRF4 /IRF4 translation.…”

Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Hypoxia‐inducible microRNA‐210 regulates the DIMT1‐IRF4 oncogenic axis in multiple myeloma

et al. 2017

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“…The Bud23-Trm112 complex is also found in human cells where TRMT112 interacts with the human Bud23 ortholog RNMT2 (also known as WBSCR22/Merm1; [74,75]). Similarly to Sc Bud23, the RNMT2 protein, but not its MTase activity, is required for ribosome biogenesis [75,76].…”

Section: Eukaryotic Trm112 Networkmentioning

confidence: 99%

“…Similarly to Sc Bud23, the RNMT2 protein, but not its MTase activity, is required for ribosome biogenesis [75,76]. RNMT2 is associated with several human diseases, as it is one of the several genes deleted in the Williams–Beuren neurodevelopmental syndrome [77,78].…”

Section: Eukaryotic Trm112 Networkmentioning

confidence: 99%

Trm112, a Protein Activator of Methyltransferases Modifying Actors of the Eukaryotic Translational Apparatus

et al. 2017

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Post-transcriptional and post-translational modifications are very important for the control and optimal efficiency of messenger RNA (mRNA) translation. Among these, methylation is the most widespread modification, as it is found in all domains of life. These methyl groups can be grafted either on nucleic acids (transfer RNA (tRNA), ribosomal RNA (rRNA), mRNA, etc.) or on protein translation factors. This review focuses on Trm112, a small protein interacting with and activating at least four different eukaryotic methyltransferase (MTase) enzymes modifying factors involved in translation. The Trm112-Trm9 and Trm112-Trm11 complexes modify tRNAs, while the Trm112-Mtq2 complex targets translation termination factor eRF1, which is a tRNA mimic. The last complex formed between Trm112 and Bud23 proteins modifies 18S rRNA and participates in the 40S biogenesis pathway. In this review, we present the functions of these eukaryotic Trm112-MTase complexes, the molecular bases responsible for complex formation and substrate recognition, as well as their implications in human diseases. Moreover, as Trm112 orthologs are found in bacterial and archaeal genomes, the conservation of this Trm112 network beyond eukaryotic organisms is also discussed.

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“…Thus it is crucial that, as researchers delve deeper into the functions of modifications in all RNA classes, the roles of the enzymes and the modifications themselves are disentangled. 79 …”

Section: Rrnamentioning

confidence: 99%

Publisher's Note

2017

RNA Biology

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RNA modifications have long been known to be central in the proper function of tRNA and rRNA. While chemical modifications in mRNA were discovered decades ago, their function has remained largely mysterious until recently. Using enrichment strategies coupled to next generation sequencing, multiple modifications have now been mapped on a transcriptome-wide scale in a variety of contexts. We now know that RNA modifications influence cell biology by many different mechanisms -by influencing RNA structure, by tuning interactions within the ribosome, and by recruiting specific binding proteins that intersect with other signaling pathways. They are also dynamic, changing in distribution or level in response to stresses such as heat shock and nutrient deprivation. Here, we provide an overview of recent themes that have emerged from the substantial progress that has been made in our understanding of chemical modifications across many major RNA classes in eukaryotes.

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The human 18S rRNA base methyltransferases DIMT1L and WBSCR22-TRMT112 but not rRNA modification are required for ribosome biogenesis

Abstract: An evolutionarily conserved quality control in ribosome biogenesis reveals that two human rRNA base methyltransferases associated with cell differentiation and cancer but, surprisingly, not their RNA-modifying activity are required for small ribosomal subunit biogenesis.

Cited by 130 publications

References 60 publications

Hypoxia‐inducible microRNA‐210 regulates the DIMT1‐IRF4 oncogenic axis in multiple myeloma

Hypoxia‐inducible microRNA‐210 regulates the DIMT1‐IRF4 oncogenic axis in multiple myeloma

Trm112, a Protein Activator of Methyltransferases Modifying Actors of the Eukaryotic Translational Apparatus

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