UIF, a New mRNA Export Adaptor that Works Together with REF/ALY, Requires FACT for Recruitment to mRNA

Hautbergue, Guillaume M.; Hung, Ming Lung; Walsh, Marianne E.; Snijders, Ambrosius P.; Chang, Chung Te; Jones, Rachel; Ponting, Chris P.; Dickman, Mark J.; Wilson, Stuart A.

doi:10.1016/j.cub.2009.09.041

Cited by 125 publications

(232 citation statements)

References 30 publications

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“…First, many cDNA-derived mRNAs are well exported despite the fact that their endogenous genes contain introns (Palazzo and Akef 2012). Second, TREX components are known to associate with intronless mRNAs in vivo and are required for their export (Rodrigues et al 2001;Taniguchi and Ohno 2008;Hautbergue et al 2009;Akef et al 2013;Lee et al 2015). Our new study, coupled with a previous report (Lee et al 2015) now resolves some of this debate.…”

Section: Discussionsupporting

confidence: 55%

Splicing promotes the nuclear export of β-globin mRNA by overcoming nuclear retention elements

Akef

Lee

Palazzo

2015

RNA

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Most current models of mRNA nuclear export in vertebrate cells assume that an mRNA must have specialized signals in order to be exported from the nucleus. Under such a scenario, mRNAs that lack these specialized signals would be shunted into a default pathway where they are retained in the nucleus and eventually degraded. These ideas were based on the selective use of model mRNA reporters. For example, it has been shown that splicing promotes the nuclear export of certain model mRNAs, such as human β-globin, and that in the absence of splicing, the cDNA-derived mRNA is retained in the nucleus and degraded. Here we provide evidence that β-globin mRNA contains an element that actively retains it in the nucleus and degrades it. Interestingly, this nuclear retention activity can be overcome by increasing the length of the mRNA or by splicing. Our results suggest that contrary to many current models, the default pathway for most intronless RNAs is to be exported from the nucleus, unless the RNA contains elements that actively promote its nuclear retention.

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Section: Discussionsupporting

confidence: 55%

Splicing promotes the nuclear export of β-globin mRNA by overcoming nuclear retention elements

Akef

Lee

Palazzo

2015

RNA

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“…The binding of Dl/Ser situated on one cell to Notch situated on the neighboring cell results in two proteolytic cleavages of Notch, which mediate the release of Notch intracellular domain (N ICD ) into the nucleus to activate Notch target gene transcription with the assistance of Su(H) and co-activator Mastermind (Mam) (Bray, 2006;Artavanis-Tsakonas and Muskavitch, 2010). Despite the relative simplicity of primary Notch signaling, the presence of a large number of fine-tuning regulators at different levels, from the outside of the cell membrane to the nucleus, dramatically increases the complexity of Notch pathway outputs and its cellular responses, thus controlling a wide range of developmental processes (Neumann and Cohen, 1998;Acar et al, 2008;Hautbergue et al, 2009;Kim et al, 2009;Xie et al, 2012). At the nuclear level, recent findings suggest that chromatin-associated regulatory mechanisms are important for proper Notch target gene expression (Bray et al, 2005;Kugler and Nagel, 2007;Moshkin et al, 2009;Duan et al, 2011;Mulligan et al, 2011;Domanitskaya and Schüpbach, 2012;Endo et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

CAF-1 promotes Notch signaling through epigenetic control of target gene expression during Drosophila development

Chen

et al. 2013

Development

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SUMMARYThe histone chaperone CAF-1 is known for its role in DNA replication-coupled histone deposition. However, loss of function causes lethality only in higher multicellular organisms such as mice and flies, but not in unicellular organisms such as yeasts, suggesting that CAF-1 has other important functions than histone deposition during animal development. Emerging evidence indicates that CAF-1 also has a role in higher order chromatin organization and heterochromatin-mediated gene expression; it remains unclear whether CAF-1 has a role in specific signaling cascades to promote gene expression during development. Here, we report that knockdown of one of the subunits of Drosophila CAF-1, dCAF-1-p105 (Caf1-105), results in phenotypes that resemble those of, and are augmented synergistically by, mutations of Notch positive regulatory pathway components. Depletion of dCAF-1-p105 leads to abrogation of cut expression and to downregulation of other Notch target genes in wing imaginal discs. dCAF-1-p105 is associated with Suppressor of Hairless [Su(H)] and regulates its binding to the enhancer region of E(spl)mβ. The association of dCAF-1-p105 with Su(H) on chromatin establishes an active local chromatin status for transcription by maintaining a high level of histone H4 acetylation. In response to induced Notch activation, dCAF-1 associates with the Notch intracellular domain to activate the expression of Notch target genes in cultured S2 cells, manifesting the role of dCAF-1 in Notch signaling. Together, our results reveal a novel epigenetic function of dCAF-1 in promoting Notch pathway activity that regulates normal Drosophila development.

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“…Different adaptors were also found to interact with the same transcripts [19] . Depletion of ALYREF is dispensable to the nuclear export of bulk mRNAs in human and Drosophila cells [19,39] and to the development of nematodes [40] . On the other hand, several of the SR-rich splicing factors play an essential role in the splicing switch that occurs during development to juvenile life.…”

Section: The Nuclear Export Of Bulk Mrnasmentioning

confidence: 99%

“…Abbreviations: REF for ALYREF; SRSF for SRSF1 or SRSF3 or SRSF7; NPC for nuclear pore complex. Other nuclear export adaptors including UAP56-interacting protein (UIF [19] ) and Leucine Zipper Protein 4 (LUZP4 [20] ) associate with TREX and are likely to play a similar role as ALYREF.…”

Section: The Nuclear Export Of Bulk Mrnasmentioning

confidence: 99%

“…TREX is composed of the subcomplex THO, DDX39B and the nuclear export adaptor ALYREF [18] . Additional factors are associated to TREX including interactions with other nuclear export adaptors [19,20] . The interactions of a varied combination of proteins and nuclear export adaptors are thought to form substitutes of TREX complexes with alternative functionalities and/or mRNA selectivity.…”

Section: The Nuclear Export Of Bulk Mrnasmentioning

confidence: 99%

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SRSF1-dependent nuclear export of C9ORF72 repeat transcripts: targeting toxic gain-of-functions induced by protein sequestration as a selective therapeutic strategy for neuroprotection

Castelli

Lin

Ferraiuolo

et al. 2018

Ther Targets Neurol Dis

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Microsatellite repeat expansions cause several incurable and lethal neurodegenerative disorders including ataxias, myotonic dystrophy, Huntington's disease and C9ORF72-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Abnormal repeat transcripts generated from the expanded loci are substrates of repeat-associated non-AUG (RAN) translation, an unconventional form of translation leading to the production of polymeric repeat proteins with cytotoxic and aggregating properties. The mechanisms involved in the pathogenesis of microsatellite repeat expansion disorders remain a hotly debated topic. They are shared between toxic loss/gain of functions due to intranuclear RNA foci that sequesters RNA-binding proteins and RAN translation of repeat proteins in the cytoplasm. We recently elucidated the molecular mechanism driving the nuclear export of C9ORF72 repeat transcripts and showed for the first time that this pathway can be manipulated to confer neuroprotection. Strikingly, we discovered that intron-retaining C9ORF72 repeat transcripts hijack the physiological NXF1-dependent export pathway by selective RNA-repeat sequestration of SRSF1. Antagonizing SRSF1 and the nuclear export of C9ORF72 repeat transcripts promoted in turn the survival of patient-derived motor neurons and suppressed neurodegeneration-associated motor deficits in Drosophila (Hautbergue et al. Nature Communications 2017; 8:16063). In this invited Research Highlight review, we aim to place this work in the context of our previous studies on the nuclear export of mRNAs, provide a summary of the published research and highlight the significance of these findings as a novel therapeutic strategy for neuroprotection in C9ORF72-ALS/FTD. In addition, we emphasize that protein sequestration, often thought as of inducing loss-of-function mechanisms, can also trigger unwanted protein interactions and toxic gain-of-functions.Keywords: Amyotrophic lateral sclerosis; Frontotemporal dementia; Neurodegeneration; Microsatellite repeat expansions; C9ORF72; RNA nuclear export; SRSF1; NXF1; RAN translation; Therapeutic strategy To cite this article: Lydia M. Castelli, et al. SRSF1-dependent nuclear export of C9ORF72 repeat-transcripts: targeting toxic gain-of-functions induced by protein sequestration as a selective therapeutic strategy for neuroprotection. Ther Targets Neurol

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UIF, a New mRNA Export Adaptor that Works Together with REF/ALY, Requires FACT for Recruitment to mRNA

Cited by 125 publications

References 30 publications

Splicing promotes the nuclear export of β-globin mRNA by overcoming nuclear retention elements

Splicing promotes the nuclear export of β-globin mRNA by overcoming nuclear retention elements

CAF-1 promotes Notch signaling through epigenetic control of target gene expression during Drosophila development

SRSF1-dependent nuclear export of C9ORF72 repeat transcripts: targeting toxic gain-of-functions induced by protein sequestration as a selective therapeutic strategy for neuroprotection

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