Luzp4 defines a new mRNA export pathway in cancer cells

Viphakone, Nicolas; Cumberbatch, Marcus; Livingstone, Michaela J.; Heath, Paul R.; Dickman, Mark J.; Catto, James W.F.; Wilson, Stuart A.

doi:10.1093/nar/gkv070

Cited by 52 publications

(56 citation statements)

References 41 publications

(72 reference statements)

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“…These can come together in different combinations to make alternative forms of TREX [14–19] (Figure 2 and Table 1). The THO subunits were originally linked to mRNP biogenesis and export through their mutant phenotypes in S. cerevisiae [31,47,48].…”

Section: The Composition Of Trexmentioning

confidence: 99%

“…Subsequently, a BLAST search revealed that LUZP4 also carries a UBM (Figure 2) and acts as an mRNA export factor associating with TREX subunits and complementing ALYREF RNAi in vivo . While the expression of LUZP4 is normally restricted to testis, it is up-regulated in melanoma cancer cells where it is required for their survival [19]. …”

Section: The Composition Of Trexmentioning

confidence: 99%

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The role of TREX in gene expression and disease

Heath

Viphakone

Wilson

2016

Biochemical Journal

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172

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TRanscription and EXport (TREX) is a conserved multisubunit complex essential for embryogenesis, organogenesis and cellular differentiation throughout life. By linking transcription, mRNA processing and export together, it exerts a physiologically vital role in the gene expression pathway. In addition, this complex prevents DNA damage and regulates the cell cycle by ensuring optimal gene expression. As the extent of TREX activity in viral infections, amyotrophic lateral sclerosis and cancer emerges, the need for a greater understanding of TREX function becomes evident. A complete elucidation of the composition, function and interactions of the complex will provide the framework for understanding the molecular basis for a variety of diseases. This review details the known composition of TREX, how it is regulated and its cellular functions with an emphasis on mammalian systems.

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Section: The Composition Of Trexmentioning

confidence: 99%

Section: The Composition Of Trexmentioning

confidence: 99%

The role of TREX in gene expression and disease

Heath

Viphakone

Wilson

2016

Biochemical Journal

Self Cite

172

222

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“…Coordinated binding of adaptors triggers a conformational switch in NXF1 that opens the loop, exposes the RBD, and enables NXF1 to bind to mRNA (Viphakone et al 2012). The model is based on studies of previously characterized NXF1 adaptor proteins, including RBM15, UIF, CHTOP, and LUZP4 as well as ALYREF, THOC5, and UAP56 of the transcription export complex (TREX) (Huang et al 2003;Taniguchi and Ohno 2008;Hautbergue et al 2009;Katahira et al 2009;Uranishi et al 2009;Walsh et al 2010;Viphakone et al 2015). Most of these adaptors recruit NXF1 to pre-mRNA 5 ′ ends via the cap-binding complex (CBC) (Cheng et al 2006;Nojima et al 2007), ensuring that exported mRNAs are capped and routing them toward the NXF1 export pathway (Müller-McNicoll and Neugebauer 2013).…”

mentioning

confidence: 99%

SR proteins are NXF1 adaptors that link alternative RNA processing to mRNA export

et al. 2016

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Nuclear export factor 1 (NXF1) exports mRNA to the cytoplasm after recruitment to mRNA by specific adaptor proteins. How and why cells use numerous different export adaptors is poorly understood. Here we critically evaluate members of the SR protein family (SRSF1-7) for their potential to act as NXF1 adaptors that couple pre-mRNA processing to mRNA export. Consistent with this proposal, >1000 endogenous mRNAs required individual SR proteins for nuclear export in vivo. To address the mechanism, transcriptome-wide RNA-binding profiles of NXF1 and SRSF1-7 were determined in parallel by individual-nucleotide-resolution UV cross-linking and immunoprecipitation (iCLIP). Quantitative comparisons of RNA-binding sites showed that NXF1 and SR proteins bind mRNA targets at adjacent sites, indicative of cobinding. SRSF3 emerged as the most potent NXF1 adaptor, conferring sequence specificity to RNA binding by NXF1 in last exons. Interestingly, SRSF3 and SRSF7 were shown to bind different sites in last exons and regulate 3 ′ untranslated region length in an opposing manner. Both SRSF3 and SRSF7 promoted NXF1 recruitment to mRNA. Thus, SRSF3 and SRSF7 couple alternative splicing and polyadenylation to NXF1-mediated mRNA export, thereby controlling the cytoplasmic abundance of transcripts with alternative 3 ′ ends.

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“…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%

“…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%

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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Luzp4 defines a new mRNA export pathway in cancer cells

Cited by 52 publications

References 41 publications

The role of TREX in gene expression and disease

The role of TREX in gene expression and disease

SR proteins are NXF1 adaptors that link alternative RNA processing to mRNA export

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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