Alternative Splicing of the First Intron of the Steroid Receptor RNA Activator (SRA) Participates in the Generation of Coding and Noncoding RNA Isoforms in Breast Cancer Cell Lines

Hubé, Florent; Guo, Jimin; Chooniedass-Kothari, Shilpa; Cooper, Charlton; Hamedani, Mohammad K.; Dibrov, Alexander; Blanchard, Anne; Wang, Xuemei; Deng, George; Myal, Yvonne; Leygue, Etienne

doi:10.1089/dna.2006.25.418

Cited by 99 publications

(126 citation statements)

References 37 publications

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“…The presence of introns in eukaryotic RNAs confers multiple degrees of flexibility in gene expression via various molecular mechanisms, such as developmental and cell-specific regulation of transcription [121], generation of non-coding RNAs [122], and alternative splicing [123]. Among these mechanisms, alternative splicing is of special interest in that it can produce two or more forms of mature mRNA from the same precursor transcript and hence generate transcripts bearing diverse information.…”

Section: Alternative Splicing Of Arabidopsis Set Genesmentioning

confidence: 99%

Plant SET domain-containing proteins: Structure, function and regulation

Wang

Chandrasekharan

et al. 2007

Biochimica et Biophysica Acta (BBA) - Gene Structure and Expres

176

195

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Modification of the histone proteins that form the core around which chromosomal DNA is looped has profound epigenetic effects on the accessibility of the associated DNA for transcription, replication and repair. The SET domain is now recognized as generally having methyltransferase activity targeted to specific lysine residues of histone H3 or H4. There is considerable sequence conservation within the SET domain and within its flanking regions. Previous reviews have shown that SET proteins from Arabidopsis and maize fall into five classes according to their sequence and domain architectures. These classes generally reflect specificity for a particular substrate. SET proteins from rice were found to fall into similar groupings, strengthening the merit of the approach taken. Two additional classes, VI and VII, were established that include proteins with truncated/ interrupted SET domains. Diverse mechanisms are involved in shaping the function and regulation of SET proteins. These include protein-protein interactions through both intra-and inter-molecular associations that are important in plant developmental processes, such as flowering time control and embryogenesis. Alternative splicing that can result in the generation of two to several different transcript isoforms is now known to be widespread. An exciting and tantalizing question is whether, or how, this alternative splicing affects gene function. For example, it is conceivable that one isoform may debilitate methyltransferase function whereas the other may enhance it, providing an opportunity for differential regulation. The review concludes with the speculation that modulation of SET protein function is mediated by antisense or sense-antisense RNA.

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Section: Alternative Splicing Of Arabidopsis Set Genesmentioning

confidence: 99%

Plant SET domain-containing proteins: Structure, function and regulation

Wang

Chandrasekharan

et al. 2007

Biochimica et Biophysica Acta (BBA) - Gene Structure and Expres

176

195

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“…NR coregulators are a group of >300 molecules that act to fine tune ligand-induced gene transcription by acting as either coactivators [e.g., steroid receptor coactivator-1 (SRC-1)] or corepressors [e.g., nuclear receptor corepressor1 (NCoR1)] (6). One of the NR coregulators, steroid receptor RNA activator (SRA), is unique, because its RNA transcript functions to coactivate NR activity (7)(8)(9).…”

mentioning

confidence: 99%

RNA-induced silencing complex (RISC) Proteins PACT, TRBP, and Dicer are SRA binding nuclear receptor coregulators

Redfern

Colley

Beveridge

et al. 2013

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

103

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The cytoplasmic RNA-induced silencing complex (RISC) contains dsRNA binding proteins, including protein kinase RNA activator (PACT), transactivation response RNA binding protein (TRBP), and Dicer, that process pre-microRNAs into mature microRNAs (miRNAs) that target specific mRNA species for regulation. There is increasing evidence for important functional interactions between the miRNA and nuclear receptor (NR) signaling networks, with recent data showing that estrogen, acting through the estrogen receptor, can modulate initial aspects of nuclear miRNA processing. Here, we show that the cytoplasmic RISC proteins PACT, TRBP, and Dicer are steroid receptor RNA activator (SRA) binding NR coregulators that target steroid-responsive promoters and regulate NR activity and downstream gene expression. Furthermore, each of the RISC proteins, together with Argonaute 2, associates with SRA and specific pre-microRNAs in both the nucleus and cytoplasm, providing evidence for links between NR-mediated transcription and some of the factors involved in miRNA processing.noncoding RNA | androgen action | prostate cancer M icroRNAs (miRNAs) are 22-nt noncoding RNAs that regulate gene expression by associating with the multiprotein RNA-induced silencing complex (RISC) and guiding RISC to silence specific mRNA species by mRNA degradation or translational inhibition (1). miRNAs are derived from large primary RNA transcripts, which are processed in the nucleus by Drosha/ Pasha into ∼70-nt precursor (pre-miRNA) duplexes. These duplexes are exported to the cytoplasm, and their conversion to mature 22-nt miRNAs is mediated by a transactivation response (TAR) RNA binding protein (TRBP)-Dicer complex (1), which provides a platform for RISC assembly and aids recruitment of Argonaute 2 (Ago2), the catalytic enzyme of RISC required for miRNA processing (2, 3). Protein kinase RNA (PKR) activator (PACT) is also integral to the RISC complex and associates with Dicer (4). TRBP and PACT are critical for efficient miRNA processing, because their depletion results in decreased mature miRNA levels and target gene silencing (2, 4, 5).Ligand-activated signaling by nuclear receptors (NRs) plays a key role in the promotion of human tumorigenesis. NR coregulators are a group of >300 molecules that act to fine tune ligand-induced gene transcription by acting as either coactivators [e.g., steroid receptor coactivator-1 (SRC-1)] or corepressors [e.g., nuclear receptor corepressor1 (NCoR1)] (6). One of the NR coregulators, steroid receptor RNA activator (SRA), is unique, because its RNA transcript functions to coactivate NR activity (7-9).Several links between miRNA pathways and NR action have been reported. miRNAs can regulate NR signaling at different levels, including targeting NRs [e.g., estrogen receptor-α (ERα)] (10, 11) or NR coregulator transcripts (e.g., amplified in breast cancer 1) (12). Conversely, NRs regulate an array of miRNAs in endocrine tissues (13). For example, ERα can regulate miRNA-21 expression at the transcriptional level (14) and the...

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“…Therefore, all of these functions could be affected by the loss of pseudouridylation of SRA by mutated PUS1p in affected erythroid precursors in the bone marrow of MLASA patients. This complex mechanism may also include differential splicing as a way of generating coding and noncoding SRA isoforms [43].…”

Section: Discussionmentioning

confidence: 99%

Pleiotropic effects and compensation mechanisms determine tissue specificity in mitochondrial myopathy and sideroblastic anemia (MLASA)

Bykhovskaya

Mengesha

Fischel‐Ghodsian

2007

Molecular Genetics and Metabolism

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The tissue specificity of mitochondrial diseases is poorly understood. Recently, tissue-specific quantitative differences of the components of the mitochondrial translation system have been found to correlate with disease presentation in fatal hepatopathy caused by mutations in mitochondrial translation factor EFG1. MLASA is an autosomal recessive inherited progressive oxidative phosphorylation disorder that affects muscle and erythroid cells. The disease is caused by the homozygous point mutation C656T (R116W) in the catalytic domain of the pseudouridylate synthase 1 (PUS1) gene, which leads to a complete lack of pseudouridylation at the expected sites in mitochondrial and cytoplasmic tRNAs. Despite the presence of these altered tRNAs, most tissues are unaffected, and even in muscle and erythroid cells the disease phenotype only slowly emerges over the course of years. In order to elucidate intracellular pathways through which the homozygous mutation leads to tissue-restricted phenotype, we performed microarray expression analysis of EBVtransformed lymphoblasts from MLASA patients, heterozygous parents, and controls using human Beadchip microarray with 47,296 transcripts. Genes coding for proteins involved in DNA transcription and its regulation, and metal binding proteins, demonstrated major differences in expression between patients and all other individuals with normal phenotype. Genes coding for ribosomal proteins differed significantly between individual with at least one copy of the mutated PUS1 gene and controls. These findings indicate that the lack of tRNA pseudouridylation can be overcome by compensatory changes in levels of ribosomal proteins, and that the disease phenotype in affected tissues is likely due to pleiotropic effects of PUS1p on non-tRNA molecules involved in DNA transcription and iron metabolism. Similar combinations of mechanisms may play a role in the tissue specificity of other mitochondrial disorders.

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Alternative Splicing of the First Intron of the Steroid Receptor RNA Activator (SRA) Participates in the Generation of Coding and Noncoding RNA Isoforms in Breast Cancer Cell Lines

Cited by 99 publications

References 37 publications

Plant SET domain-containing proteins: Structure, function and regulation

Plant SET domain-containing proteins: Structure, function and regulation

RNA-induced silencing complex (RISC) Proteins PACT, TRBP, and Dicer are SRA binding nuclear receptor coregulators

Pleiotropic effects and compensation mechanisms determine tissue specificity in mitochondrial myopathy and sideroblastic anemia (MLASA)

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