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107. Turning on the Spliceosome

Author

Hoskins, Aaron, primary, Friedman, Larry, additional, Correa, Ivan, additional, Xu, Ming-Qun, additional, Cornish, Virginia W., additional, Gelles, Jeff, additional, and Moore, Melissa J., additional

Published
2012
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108. ASC1and RPS3: new actors in 18S nonfunctional rRNA decay

Author

Limoncelli, Kelly A., Merrikh, Christopher N., and Moore, Melissa J.

Abstract

In budding yeast, inactivating mutations within the 40S ribosomal subunit decoding center lead to 18S rRNA clearance by a quality control mechanism known as nonfunctional 18S rRNA decay (18S NRD). We previously showed that 18S NRD is functionally related to No-Go mRNA Decay (NGD), a pathway for clearing translation complexes stalled on aberrant mRNAs. Whereas the NGD factors Dom34p and Hbs1p contribute to 18S NRD, their genetic deletion (either singly or in combination) only partially stabilizes mutant 18S rRNA. Here we identify Asc1p (aka RACK1) and Rps3p, both stable 40S subunit components, as additional 18S NRD factors. Complete stabilization of mutant 18S rRNA in dom34Δ;asc1Δ and hbs1Δ;asc1Δ strains indicates the existence of two genetically separable 18S NRD pathways. A small region of the Rps3p C-terminal tail known to be subject to post-translational modification is also crucial for 18S NRD. We combine these findings with the effects of mutations in the 5′ → 3′ and 3′ → 5′ decay machinery to propose a model wherein multiple targeting and decay pathways kinetically contribute to 18S NRD.

Published
2017
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109. A common class of transcripts with 5′-intron depletion, distinct early coding sequence features, and N1-methyladenosine modification

Author

Cenik, Can, Chua, Hon Nian, Singh, Guramrit, Akef, Abdalla, Snyder, Michael P., Palazzo, Alexander F., Moore, Melissa J., and Roth, Frederick P.

Abstract

Introns are found in 5′ untranslated regions (5′UTRs) for 35% of all human transcripts. These 5′UTR introns are not randomly distributed: Genes that encode secreted, membrane-bound and mitochondrial proteins are less likely to have them. Curiously, transcripts lacking 5′UTR introns tend to harbor specific RNA sequence elements in their early coding regions. To model and understand the connection between coding-region sequence and 5′UTR intron status, we developed a classifier that can predict 5′UTR intron status with >80% accuracy using only sequence features in the early coding region. Thus, the classifier identifies transcripts with 5′ proximal-intron-minus-like-coding regions (“5IM” transcripts). Unexpectedly, we found that the early coding sequence features defining 5IM transcripts are widespread, appearing in 21% of all human RefSeq transcripts. The 5IM class of transcripts is enriched for non-AUG start codons, more extensive secondary structure both preceding the start codon and near the 5′ cap, greater dependence on eIF4E for translation, and association with ER-proximal ribosomes. 5IM transcripts are bound by the exon junction complex (EJC) at noncanonical 5′ proximal positions. Finally, N1-methyladenosines are specifically enriched in the early coding regions of 5IM transcripts. Taken together, our analyses point to the existence of a distinct 5IM class comprising ∼20% of human transcripts. This class is defined by depletion of 5′ proximal introns, presence of specific RNA sequence features associated with low translation efficiency, N1-methyladenosines in the early coding region, and enrichment for noncanonical binding by the EJC.

Published
2017
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112. Dynamic and Ordered Assembly of Single Spliceosomes

Author

Hoskins, Aaron, primary, Friedman, Larry, additional, Gallagher, Sarah S., additional, Crawford, Daniel J., additional, Anderson, Eric G., additional, Wombacher, Richard, additional, Ramirez, Nicholas, additional, Cornish, Virginia W., additional, Gelles, Jeff, additional, and Moore, Melissa J., additional

Published
2011
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117. Meayamycin inhibits pre–messenger RNA splicing and exhibits picomolar activity against multidrug-resistant cells

Author

Albert, Brian J., primary, McPherson, Peter A., additional, O'Brien, Kristine, additional, Czaicki, Nancy L., additional, DeStefino, Vincent, additional, Osman, Sami, additional, Li, Miaosheng, additional, Day, Billy W., additional, Grabowski, Paula J., additional, Moore, Melissa J., additional, Vogt, Andreas, additional, and Koide, Kazunori, additional

Published
2009
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133. CRISPR/Cas9-mediated genome editing induces exon skipping by alternative splicing or exon deletion

Author

Mou, Haiwei, Smith, Jordan L., Peng, Lingtao, Yin, Hao, Moore, Jill, Zhang, Xiao-Ou, Song, Chun-Qing, Sheel, Ankur, Wu, Qiongqiong, Ozata, Deniz M., Li, Yingxiang, Anderson, Daniel G., Emerson, Charles P., Sontheimer, Erik J., Moore, Melissa J., Weng, Zhiping, and Xue, Wen

Abstract

CRISPR is widely used to disrupt gene function by inducing small insertions and deletions. Here, we show that some single-guide RNAs (sgRNAs) can induce exon skipping or large genomic deletions that delete exons. For example, CRISPR-mediated editing of β-catenin exon 3, which encodes an autoinhibitory domain, induces partial skipping of the in-frame exon and nuclear accumulation of β-catenin. A single sgRNA can induce small insertions or deletions that partially alter splicing or unexpected larger deletions that remove exons. Exon skipping adds to the unexpected outcomes that must be accounted for, and perhaps taken advantage of, in CRISPR experiments. Electronic supplementary material The online version of this article (doi:10.1186/s13059-017-1237-8) contains supplementary material, which is available to authorized users.

Published
2017
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140. Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis.

Author

Chunxing Yang, Hongyan Wang, Tao Qiao, Bin Yang, Aliaga, Leonardo, Linghua Qiu, Weijia Tan, Salameh, Johnny, McKenna-Yasek, Diane M., Smith, Thomas, Lingtao Peng, Moore, Melissa J., Brown Jr., Robert H., Huaibin Cai, and Zuoshang Xu

Subjects
AMYOTROPHIC lateral sclerosis, CENTRAL nervous system abnormality diagnosis, TREATMENT of central nervous system cancer, PHENOTYPES, CELLS, GENOTYPE-environment interaction
Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease that causes motor neuron degeneration, progressive motor dysfunction, paralysis, and death. Although multiple causes have been identified for this disease, >95% of ALS cases show aggregation of transactive response DNA binding protein (TDP-43) accompanied by its nuclear depletion. Therefore, the TDP-43 pathology may be a converging point in the pathogenesis that originates from various initial triggers. The aggregation is thought to result from TDP-43 misfolding, which could generate cellular toxicity. However, the aggregation as well as the nuclear depletion could also lead to a partial loss of TDP-43 function or TDP-43 dysfunction. To investigate the impact of TDP-43 dysfunction, we generated a transgenic mouse model for a partial loss of TDP-43 function using transgenic RNAi. These mice show ubiquitous transgene expression and TDP-43 knockdown in both the periphery and the central nervous system (CNS). Strikingly, these mice develop progressive neurodegeneration prominently in cortical layer V and spinal ventral horn, motor dysfunction, paralysis, and death. Furthermore, examination of splicing patterns of TDP-43 target genes in human ALS revealed changes consistent with TDP-43 dysfunction. These results suggest that the CNS, particularly motor neurons, possess a heightened vulnerability to TDP-43 dysfunction. Additionally, because TDP-43 knockdown predominantly occur in astrocytes in the spinal cord of these mice, our results suggest that TDP-43 dysfunction in astrocytes is an important driver for motor neuron degeneration and clinical phenotypes of ALS. [ABSTRACT FROM AUTHOR]

Published
2014
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141. Staufen1 senses overall transcript secondary structure to regulate translation.

Author

Ricci, Emiliano P, Kucukural, Alper, Cenik, Can, Mercier, Blandine C, Singh, Guramrit, Heyer, Erin E, Ashar-Patel, Ami, Peng, Lingtao, and Moore, Melissa J

Subjects
DNA-binding proteins, DOUBLE-stranded RNA, GENETIC transcription, IMMUNOPRECIPITATION, RIBOSOMES, MESSENGER RNA
Abstract

Human Staufen1 (Stau1) is a double-stranded RNA (dsRNA)-binding protein implicated in multiple post-transcriptional gene-regulatory processes. Here we combined RNA immunoprecipitation in tandem (RIPiT) with RNase footprinting, formaldehyde cross-linking, sonication-mediated RNA fragmentation and deep sequencing to map Staufen1-binding sites transcriptome wide. We find that Stau1 binds complex secondary structures containing multiple short helices, many of which are formed by inverted Alu elements in annotated 3′ untranslated regions (UTRs) or in 'strongly distal' 3′ UTRs. Stau1 also interacts with actively translating ribosomes and with mRNA coding sequences (CDSs) and 3′ UTRs in proportion to their GC content and propensity to form internal secondary structure. On mRNAs with high CDS GC content, higher Stau1 levels lead to greater ribosome densities, thus suggesting a general role for Stau1 in modulating translation elongation through structured CDS regions. Our results also indicate that Stau1 regulates translation of transcription-regulatory proteins. [ABSTRACT FROM AUTHOR]

Published
2014
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146. Single-molecule colocalization FRET evidence that spliceosome activation precedes stable approach of 5' splice site and branch site.

Author

Crawford, Daniel J., Hoskins, Aaron A., Friedman, Larry J., Gelles, Jeff, and Moore, Melissa J.

Subjects
SPLICEOSOMES, INTRONS, MESSENGER RNA, FLUORESCENCE resonance energy transfer, CATALYSIS
Abstract

Removal of introns from the precursors to messenger RNA (pre-mRNAs) requires close apposition of intron ends by the spliceosome, but when and how apposition occurs is unclear. We investigated the process by which intron ends are brought together using single-molecule fluorescence resonance energy transfer together with colocalization single-molecule spectroscopy, a combination of methods that can directly reveal how conformational transitions in macromolecular machines are coupled to specific assembly and disassembly events. The FRET measurements suggest that the 5' splice site and branch site remain physically separated throughout spliceosome assembly, and only approach one another after the spliceosome is activated for catalysis, at which time the pre-mRNA becomes highly dynamic. Separation of the sites of chemistry until very late in the splicing pathway may be crucial for preventing splicing at incorrect sites. [ABSTRACT FROM AUTHOR]

Published
2013
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147. Introns in UTRs: Why we should stop ignoring them.

Author

Bicknell, Alicia A., Cenik, Can, Chua, Hon N., Roth, Frederick P., and Moore, Melissa J.

Subjects
INTRONS, NON-coding RNA, FUNCTIONAL analysis, GENES, BIOMOLECULE analysis, MEDICAL transcription
Abstract

Although introns in 5′- and 3′-untranslated regions (UTRs) are found in many protein coding genes, rarely are they considered distinctive entities with specific functions. Indeed, mammalian transcripts with 3′-UTR introns are often assumed nonfunctional because they are subject to elimination by nonsense-mediated decay (NMD). Nonetheless, recent findings indicate that 5′- and 3′-UTR intron status is of significant functional consequence for the regulation of mammalian genes. Therefore these features should be ignored no longer. [ABSTRACT FROM AUTHOR]

Published
2012
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148. Joining RNA Molecules with T4 DNA Ligase.

Author

Walker, John M., Haynes, Susan R., and Moore, Melissa J.

Abstract

Researchers interested in studying RNA structure and function or RNA-protein interactions are increasingly using site-specifically modified RNAs to probe sites of interest (1). In addition to expanding the repertoire of functional groups beyond the very limited set available through standard mutagenesis, current synthesis techniques allow for inclusion of radioactive labels and/or various crosslinking reagents at single internal sites in RNA. The latter probes are particularly useful for determining what proteins or other RNAs interact with a site of interest on the test RNA. This chapter deals mainly with recently developed methodology for introducing such modifications into long RNAs. [ABSTRACT FROM AUTHOR]

Published
1999
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149. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis.

Author

Wu, Chi-Hong, Fallini, Claudia, Ticozzi, Nicola, Keagle, Pamela J., Sapp, Peter C., Piotrowska, Katarzyna, Lowe, Patrick, Koppers, Max, McKenna-Yasek, Diane, Baron, Desiree M., Kost, Jason E., Gonzalez-Perez, Paloma, Fox, Andrew D., Adams, Jenni, Taroni, Franco, Tiloca, Cinzia, Leclerc, Ashley Lyn, Chafe, Shawn C., Mangroo, Dev, and Moore, Melissa J.

Subjects
AMYOTROPHIC lateral sclerosis, PROFILIN, FAMILIAL diseases, GENETIC mutation, GENETIC disorders, AXONS
Abstract

Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder resulting from motor neuron death. Approximately 10% of cases are familial (FALS), typically with a dominant inheritance mode. Despite numerous advances in recent years, nearly 50% of FALS cases have unknown genetic aetiology. Here we show that mutations within the profilin 1 (PFN1) gene can cause FALS. PFN1 is crucial for the conversion of monomeric (G)-actin to filamentous (F)-actin. Exome sequencing of two large ALS families showed different mutations within the PFN1 gene. Further sequence analysis identified 4 mutations in 7 out of 274 FALS cases. Cells expressing PFN1 mutants contain ubiquitinated, insoluble aggregates that in many cases contain the ALS-associated protein TDP-43. PFN1 mutants also display decreased bound actin levels and can inhibit axon outgrowth. Furthermore, primary motor neurons expressing mutant PFN1 display smaller growth cones with a reduced F/G-actin ratio. These observations further document that cytoskeletal pathway alterations contribute to ALS pathogenesis. [ABSTRACT FROM AUTHOR]

Published
2012
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