RNA helicase DDX21 coordinates transcription and ribosomal RNA processing

Calo, Eliezer; Flynn, Ryan A.; Martin, Lance; Spitale, Robert C.; Chang, Howard Y.; Wysocka, Joanna

doi:10.1038/nature13923

Cited by 271 publications

(313 citation statements)

References 37 publications

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“…S12). Based on our data, we speculate that HEL-1 may act as a transcription coregulator, and there are precedents for the roles of RNA helicases as transcription regulators (7)(8)(9)(10). In any case, in contrast to the expectation that RNA helicases have general housekeeping roles in RNA metabolism, our findings reveal that the RNA helicase HEL-1 has specific roles in a specific longevity pathway.…”

Section: Discussioncontrasting

confidence: 51%

“…6). In addition, RNA helicases work with factors, such as a CREBbinding protein, RNA polymerases I and II, and histone deacetylases, to regulate transcriptional activity (7,8). For example, DDX5 (p68), a DEAD-box RNA helicase, interacts with Smad3, a transcriptional activator and intracellular effector of TGF-β (9), and with RNA polymerase II to modulate transcriptional activity (10).…”

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confidence: 99%

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RNA helicase HEL-1 promotes longevity by specifically activating DAF-16/FOXO transcription factor signaling in Caenorhabditis elegans

Seo

Hwang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The homeostatic maintenance of the genomic DNA is crucial for regulating aging processes. However, the role of RNA homeostasis in aging processes remains unknown. RNA helicases are a large family of enzymes that regulate the biogenesis and homeostasis of RNA. However, the functional significance of RNA helicases in aging has not been explored. Here, we report that a large fraction of RNA helicases regulate the lifespan of Caenorhabditis elegans. In particular, we show that a DEAD-box RNA helicase, helicase 1 (HEL-1), promotes longevity by specifically activating the DAF-16/forkhead box O (FOXO) transcription factor signaling pathway. We find that HEL-1 is required for the longevity conferred by reduced insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS) and is sufficient for extending lifespan. We further show that the expression of HEL-1 in the intestine and neurons contributes to longevity. HEL-1 enhances the induction of a large fraction of DAF-16 target genes. Thus, the RNA helicase HEL-1 appears to promote longevity in response to decreased IIS as a transcription coregulator of DAF-16. Because HEL-1 and IIS are evolutionarily well conserved, a similar mechanism for longevity regulation via an RNA helicase-dependent regulation of FOXO signaling may operate in mammals, including humans.arious genetic and environmental factors, including insulin/ insulin-like growth factor 1 (IGF-1) signaling (IIS), target of rapamycin signaling, dietary restriction, mitochondrial respiration, and reproductive systems, influence aging across phyla (reviewed in refs. 1-3). IIS is one of the most evolutionarily conserved pathways involved in the regulation of aging. Mutations in Caenorhabditis elegans daf-2, which encodes an insulin/IGF-1 receptor homolog, double the lifespan of C. elegans (4). Inhibition of DAF-2 reduces phosphatidylinositide 3 (PI3)-kinase signaling, which upregulates several transcription factors, including DAF-16/forkhead box O (FOXO), heat shock factor-1 (HSF-1), and SKN-1/NRF2 (reviewed in refs. 1, 3, and 5). DAF-16 is one of the best characterized of these longevity factors; reduced PI3-kinase signaling leads to the dephosphorylation and nuclear translocation of DAF-16, which up-regulates the expression of various target genes. DAF-16 target genes contribute to longevity by promoting stress resistance, reproductive span, innate immunity, and protein homeostasis.RNA helicases are essential for biogenesis, maturation, processing, and homeostasis of various types of RNAs (reviewed in ref. 6). In addition, RNA helicases work with factors, such as a CREBbinding protein, RNA polymerases I and II, and histone deacetylases, to regulate transcriptional activity (7,8). For example, DDX5 (p68), a DEAD-box RNA helicase, interacts with Smad3, a transcriptional activator and intracellular effector of TGF-β (9), and with RNA polymerase II to modulate transcriptional activity (10). Because RNA helicases comprise a large family of housekeeping proteins essential for RNA biogenesis and homeostasis, their importanc...

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Section: Discussioncontrasting

confidence: 51%

mentioning

confidence: 99%

RNA helicase HEL-1 promotes longevity by specifically activating DAF-16/FOXO transcription factor signaling in Caenorhabditis elegans

Seo

Hwang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…This is not the first time that DEAD/DEAH box proteins have been found to regulate gene transcription. Recently, a study showed that DDX21 binds 7SK RNA and is recruited to the promoters of Pol II-transcribed genes encoding ribosomal proteins and snoRNAs (21). Our results further strengthen the concept that DEAD/DEAH box proteins cannot only influence RNA metabolism but also shape DNA transcription.…”

Section: Discussionsupporting

confidence: 82%

DHX33 Transcriptionally Controls Genes Involved in the Cell Cycle

Yuan

Wang

Fan

et al. 2016

Molecular and Cellular Biology

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The RNA helicase DHX33 has been shown to be a critical regulator of cell proliferation and growth. However, the underlying mechanisms behind DHX33 function remain incompletely understood. We present original evidence in multiple cell lines that DHX33 transcriptionally controls the expression of genes involved in the cell cycle, notably cyclin, E2F1, cell division cycle (CDC), and minichromosome maintenance (MCM) genes. DHX33 physically associates with the promoters of these genes and controls the loading of active RNA polymerase II onto these promoters. DHX33 deficiency abrogates cell cycle progression and DNA replication and leads to cell apoptosis. In zebrafish, CRISPR-mediated knockout of DHX33 results in downregulation of cyclin A2, cyclin B2, cyclin D1, cyclin E2, cdc6, cdc20, E2F1, and MCM complexes in DHX33 knockout embryos. Additionally, we found the overexpression of DHX33 in a subset of non-small-cell lung cancers and in Ras-mutated human lung cancer cell lines. Forced reduction of DHX33 in these cancer cells abolished tumor formation in vivo. Our study demonstrates for the first time that DHX33 acts as a direct transcriptional regulator to promote cell cycle progression and plays an important role in driving cell proliferation during both embryo development and tumorigenesis.

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“…Indeed, we have previously shown that the Pf1 complex modulates RNAPII-driven transcription. In that aspect, it is important to note that recent findings have demonstrated that specific factors can coordinate the transcriptional regulation of ribosomal proteins and rRNA maturation (48). Our results suggest that Pf1 and its associated chromatin-modifying activities may also coordinate several steps in the generation of functional ribosomal subunits.…”

Section: Discussionmentioning

confidence: 61%

The Chromatin-Associated Phf12 Protein Maintains Nucleolar Integrity and Prevents Premature Cellular Senescence

Graveline

Marcinkiewicz

Choi

et al. 2017

Molecular and Cellular Biology

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Pf1, also known as Phf12 (plant homeodomain [PHD] zinc finger protein 12), is a member of the PHD zinc finger family of proteins. Pf1 associates with a chromatin-interacting protein complex comprised of MRG15, Sin3B, and histone deacetylase 1 (HDAC1) that functions as a transcriptional modulator. The biological function of Pf1 remains largely elusive. We undertook the generation of Pf1 knockout mice to elucidate its physiological role. We demonstrate that Pf1 is required for mid-to late gestation viability. Pf1 inactivation impairs the proliferative potential of mouse embryonic fibroblasts (MEFs) and is associated with a significant decrease in bromodeoxyuridine incorporation; an increase in senescence-associated ␤-galactosidase (SA-␤-Gal) activity, a marker of cellular senescence; and elevated levels of phosphorylated H2AX (␥-H2A.X), a marker associated with DNA double-strand breaks. Analysis of transcripts differentially expressed in wild-type and Pf1-deficient cells revealed the impact of Pf1 in multiple regulatory arms of the ribosome biogenesis pathways. Strikingly, assessment of the morphology of the nucleoli exposed an abnormal nucleolar structure in Pf1-deficient cells. Finally, proteomic analysis of the Pf1-interacting complexes highlighted proteins involved in ribosome biogenesis. Taken together, our data reveal an unsuspected function for the Pf1-associated chromatin complex in the ribosomal biogenesis and senescence pathways.KEYWORDS transcription, ribosome, Pf1, senescence, nucleolus P f1, also known as Phf12 (plant homeodomain [PHD] zinc finger protein 12), is a member of the PHD zinc finger family of proteins. PHD domains are small, 50-to 80-amino-acid-long domains often found in clusters of two or three and/or in the proximity of other chromatin-interacting domains, such as bromo-or chromodomains. Consistently, many of the PHD-containing proteins are nuclear proteins that interact with chromatin. Increasing evidence suggests that PHD domains are capable of recognizing modified and unmodified histone tails and that PHD domain-containing proteins act as epigenetic readers (1).The Pf1 gene is conserved throughout evolution, and the Pf1 protein, like its Saccharomyces cerevisiae yeast homolog, Rco1, contains two PHD domains in its N terminus. Mammalian Pf1 was first identified in a yeast two-hybrid screen for proteins interacting with the paired amphipathic helix 2 (PAH2) domain of Sin3A and shown to function as a transcriptional repressor (2). A later report identified Pf1 to be one of the components of the human MRG15 complex, together with Sin3B but not together with its close homolog, Sin3A (3). The PHD domains of Pf1 are important for the interaction with the MRG domain of MRG15, which relies mainly on hydrophobic interactions (3-5). The interaction of Pf1 with a complex containing Sin3B but not Sin3A was also confirmed in experiments identifying associations between Sin3B, histone deacetylase

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RNA helicase DDX21 coordinates transcription and ribosomal RNA processing

Cited by 271 publications

References 37 publications

RNA helicase HEL-1 promotes longevity by specifically activating DAF-16/FOXO transcription factor signaling in Caenorhabditis elegans

RNA helicase HEL-1 promotes longevity by specifically activating DAF-16/FOXO transcription factor signaling in Caenorhabditis elegans

DHX33 Transcriptionally Controls Genes Involved in the Cell Cycle

The Chromatin-Associated Phf12 Protein Maintains Nucleolar Integrity and Prevents Premature Cellular Senescence

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