Poison exon

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Certain transcripts contain poison exons that can be incorporated via alternative splicing. Skipping of the poison exon leads to a productive transcript that is translated to protein. Incorporation of the poison exon introduces a premature termination codon into the transcript that leads to degradation of the transcript via nonsense-mediated decay. (PDB: 2N3L) Poison exon.png
Certain transcripts contain poison exons that can be incorporated via alternative splicing. Skipping of the poison exon leads to a productive transcript that is translated to protein. Incorporation of the poison exon introduces a premature termination codon into the transcript that leads to degradation of the transcript via nonsense-mediated decay. (PDB: 2N3L)

Poison exons (PEs); also called premature termination codon (PTC) exons or nonsense-mediated decay (NMD) exons] are a class of cassette exons that contain PTCs. Inclusion of a PE in a transcript targets the transcript for degradation via NMD. PEs are generally highly conserved elements of the genome and are thought to have important regulatory roles in biology. [1] [2] Targeting PE inclusion or exclusion in certain transcripts is being evaluated as a therapeutic strategy.

Contents

Discovery

In 2002, a model termed regulated unproductive splicing and translation (RUST) was proposed based on the finding that many (~one-third) alternatively spliced transcripts contain PEs. In this model, coupling alternative splicing to NMD (AS-NMD) is thought to tune transcript levels to regulate protein expression. [3] Alternative splicing may also lead to NMD via other pathways besides PE inclusion, e.g., intron retention. [4] [5]

PEs were initially characterized in RNA-binding proteins from the SR protein family. [1] [2] Genes for other RNA-binding proteins (RBPs) such as those for heterogenous nuclear ribonucleoprotein (hnRNP) also contain PEs. [2] Numerous chromatin regulators also contain PEs, though these are less conserved than PEs within RBPs such as the SR proteins. [6] Multiple spliceosomal components contain PEs. [7]

PE-containing transcripts generally represent a minority of the overall transcript population, in part due to their active degradation via NMD, though this relative abundance can be elevated upon inhibition of NMD or certain biological states. [2] [8] [9] [10] [11] Certain PE-containing transcripts are resistant to NMD and may be translated into truncated proteins. [12]

Regulation

Cis-regulatory elements neighboring PEs have been found to affect PE inclusion. [13]

Many proteins whose corresponding genes contain PEs autoregulate PE inclusion in their respective transcripts and thereby control their own levels via a feedback loop. [12] [14] [15] [16] [17] [18] [19] Cross-regulation of PE inclusion has also been observed. [20] [21] [22]

Differential splicing of PEs is implicated in biological processes such as differentiation, [23] [24] neurodevelopment, [25] dispersal of nuclear speckles during hypoxia, [26] tumorigenesis, [24] [27] organism growth, [15] and T cell expansion. [28]

Protein kinases that regulate phosphorylation of splicing factors can affect splicing processes, thus kinase inhibitors may affect inclusion of PEs. For example, CMGC kinase inhibitors and CDK9 inhibitors have been found to induce PE inclusion in RBM39 . [29]

Small molecules that modulate chromatin accessibility can affect PE inclusion. [30]

Mutations in splicing factors can lead to inclusion of PEs in certain transcripts. [31]

PE inclusion can be regulated by external variables such as temperature and electrical activity. For example, PE inclusion in RBM3 transcript is lowered during hypothermia. This is mediated by temperature-dependent binding of the splicing factor HNRNPH1 to the RBM3 transcript. [9] The neuronal RBPs NOVA1/2 are translocated from the nucleus to the cytoplasm during pilocarpine-induced seizure in mice, and it was found that NOVA1/2 regulates the expression of cryptic PEs. [32] The glycosyltransferase O-GlcNAc transferase is responsible for installing the O-GlcNAc post-translational modification and contains a PE. [33] It has been frequently observed that pharmacological or genetic perturbations that elevate cellular O-GlcNAc levels increase PE inclusion in the OGT transcript. [34]

Disease

Proper regulation of PE inclusion and exclusion is important for health. Genetic mutations can affect inclusion of PEs and cause disease. For example, loss of CCAR1 leads to PE inclusion in the FANCA transcript, resulting in a Fanconi anemia phenotype. [35]

Dysregulation of components of the splicing machinery can also cause dysregulation of PE inclusion. Mutations in the splicing factor SF3B1 have been found to promote PE inclusion in BRD9 , reducing BRD9 mRNA and protein levels and leading to melanomagenesis. [36] Mutations in U2AF1 promote PE inclusion in EIF4A2 , leading to impaired global mRNA translation and acute myeloid leukemia (AML) chemoresistance through the integrated stress response pathway. [37] The splicing factor SRSF6 contains a PE whose skipping is connected to T cell acute lymphoblastic leukemia (T-ALL), [38] and PE inclusion in SRSF10 is linked to acute lymphoblastic leukemia (ALL). [39]

Intronic mutations can lead to PE inclusion, such as in the case of SCN1A , where mutations within intron 20 promote inclusion of the nearby PE 20N, leading to Dravet syndrome-like phenotypes in mouse models. [40] [41] An intronic mutation in FLNA has been found to impair binding of the splicing regulator PTBP1, leading to inclusion of a poison exon in FLNA transcripts that causes a brain-specific malformation. [25]

Differential inclusion of PEs in various splicing factor and hnRNP genes has been reported in type 1 diabetes. [42] SRSF2 mutations have been found to promote PE inclusion in the epigenetic regulator EZH2 , resulting in impaired hematopoietic differentiation. [43]

Clinical relevance

Diagnostics

With the advent of next-generation sequencing technologies, [44] diagnostic genetic testing has emerged as a powerful tool to diagnose afflictions associated with specific genetic variants. Many diagnostic genetic testing efforts have focused on exome sequencing. [45] PE annotations may improve the diagnostic yield of these tests for certain diseases. For example, variants that affect PE inclusion in sodium channel genes (SCN1A, SCN2A , and SCN8A ) have been found to be associated with epilepsies, and analogous variants in SNRPB have been found to be associated with cerebrocostomandibular syndrome. [46] [47]

Therapeutic discovery

As PE inclusion results in transcript degradation, targeted PE inclusion or exclusion is being evaluated as a therapeutic strategy. [48] This strategy may prove especially applicable towards targets whose gene products are not easily ligandable such as "undruggable" proteins. Targeting PE inclusion/exlusion has been demonstrated with both small molecules [49] [50] and antisense oligonucleotides (ASOs). [24] [51] Small molecules may modulate splicing by stabilizing alternative splice sites. [49] [52] ASOs may block specific splice sites or target certain cis-regulatory elements to promote splicing at other sites. [53] [54] These ASOs may also be referred to as splice-switching oligonucleotides (SSOs). [24] [54] ASO walks tiling different ASOs across a gene sequence may be necessary to identify ASOs that have the desired effect on PE inclusion. [51]

Stoke Therapeutics is evaluating a strategy termed Targeted Augmentation of Nuclear Gene Output (TANGO). [51] Targeting exon 20N in SCN1A mRNA with the antisense oligonucleotide zorevunersen (STK-001) blocks inclusion of this PE, leading to elevated levels of the productive SCN1A transcript and the gene product sodium channel protein 1 subunit alpha (NaV1.1). In mouse models of Dravet syndrome, which is driven by mutations in SCN1A, [40] [41] [55] zorevunersen was able to reduce incidence of electrographic seizures and sudden unexpected death in epilepsy and prolong survival. [56] [57] As of October 2024, zorevunersen is being evaluated in phase 2 clinical trials (NCT04740476). [58] Zorevunersen received FDA Breakthrough Therapy Designation in December 2024. [59] Also in December 2024, Stoke Therapeutics disclosed that zorevunersen is generally well tolerated and shows substantial and sustained reductions in convulsive seizure frequency. [60] Stoke Therapeutics expects to launch a phase 3 clinical trial in 2025 evaluating zorevunersen for reduction in seizure frequency as the primary endpoint and cognition and behavioral changes as secondary endpoints. [61]

Stoke Therapeutics is also evaluating the ASO STK-002 for treatment of autosomal dominant optic atrophy (ADOA). STK-002 promotes removal of a PE in the transcript of OPA1 , leading to elevated OPA1 protein levels. [62]

Remix Therapeutics developed REM-422, which is an oral small molecule that promotes PE inclusion in the oncogene MYB . REM-422 was discovered through a screening campaign for molecules that promote PE inclusion in MYB. Subsequent in vitro experiments showed that REM-422 selectively facilitates binding of the U1 snRNP complex to oligonucleotides containing the MYB 5' splice site sequence. In various AML cell lines, REM-422 leads to degradation of MYB mRNA and lower MYB protein levels. REM-422 demonstrated antitumor activity in mouse xenograft models of acute myeloid leukemia. [49] As of October 2024, REM-422 is being evaluated in phase 1 clinical trials (NCT06118086, NCT06297941). [63] [64] The splicing modulator small molecule risdiplam, originally developed to promote exon 7 inclusion in the SMN2 transcript for treatment of spinal muscular atrophy, [65] [66] dose-dependently promotes PE inclusion in the MYB transcript as well. [67]

Rgenta Therapeutics has also developed RGT-61159, an oral small molecule that promotes PE inclusion in MYB, as a potential treatment for adenoid cystic carcinoma (ACC). [68] RGT-61159 is being evaluated in phase 1 clinical trials (NCT06462183). [69]

PTC Therapeutics is evaluating the oral small molecule PTC518 as a treatment for Huntington's disease. [50] PTC518 was well-tolerated and showed dose-dependent decreases in HTT mRNA and HTT protein levels in a phase 1 clinical trial. [70] As of October 2024, PTC518 is being evaluated in phase 2 clinical trials (NCT05358717). [71] In December 2024, Novartis entered a global license and collaboration agreement with PTC Therapeutics for PTC518 with an upfront payment of $1.0 billion and up to $1.9 billion in development, regulatory, and sales milestones. [72]

Therapeutic targeting of poison exon inclusion/exclusion has also been proposed for oncogenic splicing factors, [24] [27] BRD9 (for treatment of cancer), [36] SYNGAP1, [73] RBM3 (for treatment of neurodegeneration), [53] and CFTR (for treatment of cystic fibrosis). [74]

Related Research Articles

<span class="mw-page-title-main">Exon</span> A region of a transcribed gene present in the final functional mRNA molecule

An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term exon refers to both the DNA sequence within a gene and to the corresponding sequence in RNA transcripts. In RNA splicing, introns are removed and exons are covalently joined to one another as part of generating the mature RNA. Just as the entire set of genes for a species constitutes the genome, the entire set of exons constitutes the exome.

An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word intron is derived from the term intragenic region, i.e., a region inside a gene. The term intron refers to both the DNA sequence within a gene and the corresponding RNA sequence in RNA transcripts. The non-intron sequences that become joined by this RNA processing to form the mature RNA are called exons.

<span class="mw-page-title-main">RNA splicing</span> Process in molecular biology

RNA splicing is a process in molecular biology where a newly-made precursor messenger RNA (pre-mRNA) transcript is transformed into a mature messenger RNA (mRNA). It works by removing all the introns and splicing back together exons. For nuclear-encoded genes, splicing occurs in the nucleus either during or immediately after transcription. For those eukaryotic genes that contain introns, splicing is usually needed to create an mRNA molecule that can be translated into protein. For many eukaryotic introns, splicing occurs in a series of reactions which are catalyzed by the spliceosome, a complex of small nuclear ribonucleoproteins (snRNPs). There exist self-splicing introns, that is, ribozymes that can catalyze their own excision from their parent RNA molecule. The process of transcription, splicing and translation is called gene expression, the central dogma of molecular biology.

<span class="mw-page-title-main">Alternative splicing</span> Process by which a gene can code for multiple proteins

Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene may be included within or excluded from the final RNA product of the gene. This means the exons are joined in different combinations, leading to different splice variants. In the case of protein-coding genes, the proteins translated from these splice variants may contain differences in their amino acid sequence and in their biological functions.

<span class="mw-page-title-main">Protein isoform</span> Forms of a protein produced from different genes

A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have unique functions. A set of protein isoforms may be formed from alternative splicings, variable promoter usage, or other post-transcriptional modifications of a single gene; post-translational modifications are generally not considered. Through RNA splicing mechanisms, mRNA has the ability to select different protein-coding segments (exons) of a gene, or even different parts of exons from RNA to form different mRNA sequences. Each unique sequence produces a specific form of a protein.

<span class="mw-page-title-main">Morpholino</span> Chemical compound

A Morpholino, also known as a Morpholino oligomer and as a phosphorodiamidate Morpholino oligomer (PMO), is a type of oligomer molecule used in molecular biology to modify gene expression. Its molecular structure contains DNA bases attached to a backbone of methylenemorpholine rings linked through phosphorodiamidate groups. Morpholinos block access of other molecules to small specific sequences of the base-pairing surfaces of ribonucleic acid (RNA). Morpholinos are used as research tools for reverse genetics by knocking down gene function.

Trans-splicing is a special form of RNA processing where exons from two different primary RNA transcripts are joined end to end and ligated. It is usually found in eukaryotes and mediated by the spliceosome, although some bacteria and archaea also have "half-genes" for tRNAs.

<span class="mw-page-title-main">SR protein</span>

SR proteins are a conserved family of proteins involved in RNA splicing. SR proteins are named because they contain a protein domain with long repeats of serine and arginine amino acid residues, whose standard abbreviations are "S" and "R" respectively. SR proteins are ~200-600 amino acids in length and composed of two domains, the RNA recognition motif (RRM) region and the RS domain. SR proteins are more commonly found in the nucleus than the cytoplasm, but several SR proteins are known to shuttle between the nucleus and the cytoplasm.

<span class="mw-page-title-main">Nonsense-mediated decay</span> Elimination of mRNA with premature stop codons in eukaryotes

Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that exists in all eukaryotes. Its main function is to reduce errors in gene expression by eliminating mRNA transcripts that contain premature stop codons. Translation of these aberrant mRNAs could, in some cases, lead to deleterious gain-of-function or dominant-negative activity of the resulting proteins.

Dravet syndrome (DS), previously known as severe myoclonic epilepsy of infancy (SMEI), is an autosomal dominant genetic disorder which causes a catastrophic form of epilepsy, with prolonged seizures that are often triggered by hot temperatures or fever. It is very difficult to treat with anticonvulsant medications. It often begins before one year of age, with six months being the age that seizures, char­ac­ter­ized by prolonged convulsions and triggered by fever, usually begin.

An exonic splicing silencer (ESS) is a short region of an exon and is a cis-regulatory element. A set of 103 hexanucleotides known as FAS-hex3 has been shown to be abundant in ESS regions. ESSs inhibit or silence splicing of the pre-mRNA and contribute to constitutive and alternate splicing. To elicit the silencing effect, ESSs recruit proteins that will negatively affect the core splicing machinery.

SCN1A Protein-coding gene in the species Homo sapiens

Sodium channel protein type 1 subunit alpha (SCN1A), is a protein which in humans is encoded by the SCN1A gene.

<span class="mw-page-title-main">TRA2B</span> Protein-coding gene in the species Homo sapiens

Transformer-2 protein homolog beta, also known as TRA2B previously known as splicing factor, arginine/serine-rich 10 (SFRS10), is a protein that in humans is encoded by the TRA2B gene.

<span class="mw-page-title-main">UPF2</span> Protein-coding gene in the species Homo sapiens

Regulator of nonsense transcripts 2 is a protein that in humans is encoded by the UPF2 gene.

<span class="mw-page-title-main">UPF3B</span> Protein-coding gene in the species Homo sapiens

Regulator of nonsense transcripts 3B is a protein that in humans is encoded by the UPF3B gene.

<span class="mw-page-title-main">UPF3A</span> Protein-coding gene in the species Homo sapiens

Regulator of nonsense transcripts 3A is a protein that in humans is encoded by the UPF3A gene.

<span class="mw-page-title-main">RBM9</span> Protein-coding gene in the species Homo sapiens

RNA binding motif protein 9 (RBM9), also known as Rbfox2, is a protein which in humans is encoded by the RBM9 gene.

<span class="mw-page-title-main">RBFOX1</span> Protein-coding gene in the species Homo sapiens

Fox-1 homolog A, also known as ataxin 2-binding protein 1 (A2BP1) or hexaribonucleotide-binding protein 1 (HRNBP1) or RNA binding protein, fox-1 homolog (Rbfox1), is a protein that in humans is encoded by the RBFOX1 gene.

mRNA surveillance mechanisms are pathways utilized by organisms to ensure fidelity and quality of messenger RNA (mRNA) molecules. There are a number of surveillance mechanisms present within cells. These mechanisms function at various steps of the mRNA biogenesis pathway to detect and degrade transcripts that have not properly been processed.

<span class="mw-page-title-main">Exon junction complex</span> Protein complex assembled on mRNA

An exon junction complex (EJC) is a protein complex which forms on a pre-messenger RNA strand at the junction of two exons which have been joined together during RNA splicing. The EJC has major influences on translation, surveillance, localization of the spliced mRNA, and m6A methylation. It is first deposited onto mRNA during splicing and is then transported into the cytoplasm. There it plays a major role in post-transcriptional regulation of mRNA. It is believed that exon junction complexes provide a position-specific memory of the splicing event. The EJC consists of a stable heterotetramer core, which serves as a binding platform for other factors necessary for the mRNA pathway. The core of the EJC contains the protein eukaryotic initiation factor 4A-III bound to an adenosine triphosphate (ATP) analog, as well as the additional proteins Magoh and Y14. The binding of these proteins to nuclear speckled domains has been measured recently and it may be regulated by PI3K/AKT/mTOR signaling pathways. In order for the binding of the complex to the mRNA to occur, the eIF4AIII factor is inhibited, stopping the hydrolysis of ATP. This recognizes EJC as an ATP dependent complex. EJC also interacts with a large number of additional proteins; most notably SR proteins. These interactions are suggested to be important for mRNA compaction. The role of EJC in mRNA export is controversial.

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