RNA splicing

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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 (non-coding regions of RNA) and splicing back together exons (coding regions). 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.

Contents

Process of RNA splicing Process of RNA splicing.png
Process of RNA splicing

Splicing pathways

Several methods of RNA splicing occur in nature; the type of splicing depends on the structure of the spliced intron and the catalysts required for splicing to occur.

Spliceosomal complex

Introns

The word intron is derived from the terms intragenic region, [1] and intracistron, [2] that is, a segment of DNA that is located between two exons of a gene. The term intron refers to both the DNA sequence within a gene and the corresponding sequence in the unprocessed RNA transcript. As part of the RNA processing pathway, introns are removed by RNA splicing either shortly after or concurrent with transcription. [3] Introns are found in the genes of most organisms and many viruses. They can be located in a wide range of genes, including those that generate proteins, ribosomal RNA (rRNA), and transfer RNA (tRNA). [4]

Within introns, a donor site (5' end of the intron), a branch site (near the 3' end of the intron) and an acceptor site (3' end of the intron) are required for splicing. The splice donor site includes an almost invariant sequence GU at the 5' end of the intron, within a larger, less highly conserved region. The splice acceptor site at the 3' end of the intron terminates the intron with an almost invariant AG sequence. Upstream (5'-ward) from the AG there is a region high in pyrimidines (C and U), or polypyrimidine tract. Further upstream from the polypyrimidine tract is the branchpoint, which includes an adenine nucleotide involved in lariat formation. [5] [6] The consensus sequence for an intron (in IUPAC nucleic acid notation) is: G-G-[cut]-G-U-R-A-G-U (donor site) ... intron sequence ... Y-U-R-A-C (branch sequence 20-50 nucleotides upstream of acceptor site) ... Y-rich-N-C-A-G-[cut]-G (acceptor site). [7] However, it is noted that the specific sequence of intronic splicing elements and the number of nucleotides between the branchpoint and the nearest 3’ acceptor site affect splice site selection. [8] [9] Also, point mutations in the underlying DNA or errors during transcription can activate a cryptic splice site in part of the transcript that usually is not spliced. This results in a mature messenger RNA with a missing section of an exon. In this way, a point mutation, which might otherwise affect only a single amino acid, can manifest as a deletion or truncation in the final protein.

Intron Exon Boundary in pre-mRNA 1 - 3' Splice site 2 - Poly pyrimidine Tract 3 - Branch site 4 - 5' splice site Intron miguelferig.jpg
Intron Exon Boundaryin pre-mRNA 1 - 3' Splice site 2 - Poly pyrimidine Tract 3 - Branch site 4 - 5' splice site

Formation and activity

Splicing is catalyzed by the spliceosome, a large RNA-protein complex composed of five small nuclear ribonucleoproteins (snRNPs). Assembly and activity of the spliceosome occurs during transcription of the pre-mRNA. The RNA components of snRNPs interact with the intron and are involved in catalysis. Two types of spliceosomes have been identified (major and minor) which contain different snRNPs.

  • The major spliceosome splices introns containing GU at the 5' splice site and AG at the 3' splice site. It is composed of the U1, U2, U4, U5, and U6 snRNPs and is active in the nucleus. In addition, a number of proteins including U2 small nuclear RNA auxiliary factor 1 (U2AF35), U2AF2 (U2AF65) [10] and SF1 are required for the assembly of the spliceosome. [6] [11] The spliceosome forms different complexes during the splicing process: [12]
  • Complex E
    • The U1 snRNP binds to the GU sequence at the 5' splice site of an intron;
    • Splicing factor 1 binds to the intron branch point sequence;
    • U2AF1 binds at the 3' splice site of the intron;
    • U2AF2 binds to the polypyrimidine tract; [13]
  • Complex A (pre-spliceosome)
    • The U2 snRNP displaces SF1 and binds to the branch point sequence and ATP is hydrolyzed;
  • Complex B (pre-catalytic spliceosome)
    • The U5/U4/U6 snRNP trimer binds, and the U5 snRNP binds exons at the 5' site, with U6 binding to U2;
  • Complex B*
    • The U1 snRNP is released, U5 shifts from exon to intron, and the U6 binds at the 5' splice site;
  • Complex C (catalytic spliceosome)
    • U4 is released, U6/U2 catalyzes transesterification, making the 5'-end of the intron ligate to the A on intron and form a lariat, U5 binds exon at 3' splice site, and the 5' site is cleaved, resulting in the formation of the lariat;
  • Complex C* (post-spliceosomal complex)
    • U2/U5/U6 remain bound to the lariat, and the 3' site is cleaved and exons are ligated using ATP hydrolysis. The spliced RNA is released, the lariat is released and degraded, [14] and the snRNPs are recycled.
This type of splicing is termed canonical splicing or termed the lariat pathway, which accounts for more than 99% of splicing. By contrast, when the intronic flanking sequences do not follow the GU-AG rule, noncanonical splicing is said to occur (see "minor spliceosome" below). [15]
  • The minor spliceosome is very similar to the major spliceosome, but instead it splices out rare introns with different splice site sequences. While the minor and major spliceosomes contain the same U5 snRNP, the minor spliceosome has different but functionally analogous snRNPs for U1, U2, U4, and U6, which are respectively called U11, U12, U4atac, and U6atac. [16]

Recursive splicing

In most cases, splicing removes introns as single units from precursor mRNA transcripts. However, in some cases, especially in mRNAs with very long introns, splicing happens in steps, with part of an intron removed and then the remaining intron is spliced out in a following step. This has been found first in the Ultrabithorax (Ubx) gene of the fruit fly, Drosophila melanogaster , and a few other Drosophila genes, but cases in humans have been reported as well. [17] [18]

Trans-splicing

Trans-splicing is a form of splicing that removes introns or outrons, and joins two exons that are not within the same RNA transcript. [19] Trans-splicing can occur between two different endogenous pre-mRNAs or between an endogenous and an exogenous (such as from viruses) or artificial RNAs. [20]

Self-splicing

Self-splicing occurs for rare introns that form a ribozyme, performing the functions of the spliceosome by RNA alone. There are three kinds of self-splicing introns, Group I , Group II and Group III . Group I and II introns perform splicing similar to the spliceosome without requiring any protein. This similarity suggests that Group I and II introns may be evolutionarily related to the spliceosome. Self-splicing may also be very ancient, and may have existed in an RNA world present before protein.

Two transesterifications characterize the mechanism in which group I introns are spliced:

  1. 3'OH of a free guanine nucleoside (or one located in the intron) or a nucleotide cofactor (GMP, GDP, GTP) attacks phosphate at the 5' splice site.
  2. 3'OH of the 5' exon becomes a nucleophile and the second transesterification results in the joining of the two exons.

The mechanism in which group II introns are spliced (two transesterification reaction like group I introns) is as follows:

  1. The 2'OH of a specific adenosine in the intron attacks the 5' splice site, thereby forming the lariat
  2. The 3'OH of the 5' exon triggers the second transesterification at the 3' splice site, thereby joining the exons together.

tRNA splicing

tRNA (also tRNA-like) splicing is another rare form of splicing that usually occurs in tRNA. The splicing reaction involves a different biochemistry than the spliceosomal and self-splicing pathways.

In the yeast Saccharomyces cerevisiae , a yeast tRNA splicing endonuclease heterotetramer, composed of TSEN54, TSEN2, TSEN34, and TSEN15, cleaves pre-tRNA at two sites in the acceptor loop to form a 5'-half tRNA, terminating at a 2',3'-cyclic phosphodiester group, and a 3'-half tRNA, terminating at a 5'-hydroxyl group, along with a discarded intron. [21] Yeast tRNA kinase then phosphorylates the 5'-hydroxyl group using adenosine triphosphate. Yeast tRNA cyclic phosphodiesterase cleaves the cyclic phosphodiester group to form a 2'-phosphorylated 3' end. Yeast tRNA ligase adds an adenosine monophosphate group to the 5' end of the 3'-half and joins the two halves together. [22] NAD-dependent 2'-phosphotransferase then removes the 2'-phosphate group. [23] [24]

Evolution

Splicing occurs in all the kingdoms or domains of life, however, the extent and types of splicing can be very different between the major divisions. Eukaryotes splice many protein-coding messenger RNAs and some non-coding RNAs. Prokaryotes, on the other hand, splice rarely and mostly non-coding RNAs. Another important difference between these two groups of organisms is that prokaryotes completely lack the spliceosomal pathway.

Because spliceosomal introns are not conserved in all species, there is debate concerning when spliceosomal splicing evolved. Two models have been proposed: the intron late and intron early models (see intron evolution).

Splicing diversity
EukaryotesProkaryotes
Spliceosomal+−
Self-splicing++
tRNA++

Biochemical mechanism

Diagram illustrating the two-step biochemistry of splicing RNA splicing reaction.svg
Diagram illustrating the two-step biochemistry of splicing

Spliceosomal splicing and self-splicing involve a two-step biochemical process. Both steps involve transesterification reactions that occur between RNA nucleotides. tRNA splicing, however, is an exception and does not occur by transesterification. [25]

Spliceosomal and self-splicing transesterification reactions occur via two sequential transesterification reactions. First, the 2'OH of a specific branchpoint nucleotide within the intron, defined during spliceosome assembly, performs a nucleophilic attack on the first nucleotide of the intron at the 5' splice site, forming the lariat intermediate. Second, the 3'OH of the released 5' exon then performs a nucleophilic attack at the first nucleotide following the last nucleotide of the intron at the 3' splice site, thus joining the exons and releasing the intron lariat. [26]

Alternative splicing

In many cases, the splicing process can create a range of unique proteins by varying the exon composition of the same mRNA. This phenomenon is then called alternative splicing. Alternative splicing can occur in many ways. Exons can be extended or skipped, or introns can be retained. It is estimated that 95% of transcripts from multiexon genes undergo alternative splicing, some instances of which occur in a tissue-specific manner and/or under specific cellular conditions. [27] Development of high throughput mRNA sequencing technology can help quantify the expression levels of alternatively spliced isoforms. Differential expression levels across tissues and cell lineages allowed computational approaches to be developed to predict the functions of these isoforms. [28] [29] Given this complexity, alternative splicing of pre-mRNA transcripts is regulated by a system of trans-acting proteins (activators and repressors) that bind to cis-acting sites or "elements" (enhancers and silencers) on the pre-mRNA transcript itself. These proteins and their respective binding elements promote or reduce the usage of a particular splice site. The binding specificity comes from the sequence and structure of the cis-elements, e.g. in HIV-1 there are many donor and acceptor splice sites. Among the various splice sites, ssA7, which is 3' acceptor site, folds into three stem loop structures, i.e. Intronic splicing silencer (ISS), Exonic splicing enhancer (ESE), and Exonic splicing silencer (ESSE3). Solution structure of Intronic splicing silencer and its interaction to host protein hnRNPA1 give insight into specific recognition. [30] However, adding to the complexity of alternative splicing, it is noted that the effects of regulatory factors are many times position-dependent. For example, a splicing factor that serves as a splicing activator when bound to an intronic enhancer element may serve as a repressor when bound to its splicing element in the context of an exon, and vice versa. [31] In addition to the position-dependent effects of enhancer and silencer elements, the location of the branchpoint (i.e., distance upstream of the nearest 3’ acceptor site) also affects splicing. [8] The secondary structure of the pre-mRNA transcript also plays a role in regulating splicing, such as by bringing together splicing elements or by masking a sequence that would otherwise serve as a binding element for a splicing factor. [32] [33]

Role of splicing/alternative splicing in HIV-integration

The process of splicing is linked with HIV integration, as HIV-1 targets highly spliced genes. [34]

Splicing response to DNA damage

DNA damage affects splicing factors by altering their post-translational modification, localization, expression and activity. [35] Furthermore, DNA damage often disrupts splicing by interfering with its coupling to transcription. DNA damage also has an impact on the splicing and alternative splicing of genes intimately associated with DNA repair. [35] For instance, DNA damages modulate the alternative splicing of the DNA repair genes Brca1 and Ercc1 .

Experimental manipulation of splicing

Splicing events can be experimentally altered [36] [37] by binding steric-blocking antisense oligos, such as Morpholinos or Peptide nucleic acids to snRNP binding sites, to the branchpoint nucleotide that closes the lariat, [38] or to splice-regulatory element binding sites. [39]

The use of antisense oligonucleotides to modulate splicing has shown great promise as a therapeutic strategy for a variety of genetic diseases caused by splicing defects. [40]

Recent studies have shown that RNA splicing can be regulated by a variety of epigenetic modifications, including DNA methylation and histone modifications. [41]

Splicing errors and variation

It has been suggested that one third of all disease-causing mutations impact on splicing. [31] Common errors include:

Although many splicing errors are safeguarded by a cellular quality control mechanism termed nonsense-mediated mRNA decay (NMD), [42] a number of splicing-related diseases also exist, as suggested above. [43]

Allelic differences in mRNA splicing are likely to be a common and important source of phenotypic diversity at the molecular level, in addition to their contribution to genetic disease susceptibility. Indeed, genome-wide studies in humans have identified a range of genes that are subject to allele-specific splicing.

In plants, variation for flooding stress tolerance correlated with stress-induced alternative splicing of transcripts associated with gluconeogenesis and other processes. [44]

Protein splicing

In addition to RNA, proteins can undergo splicing. Although the biomolecular mechanisms are different, the principle is the same: parts of the protein, called inteins instead of introns, are removed. The remaining parts, called exteins instead of exons, are fused together. Protein splicing has been observed in a wide range of organisms, including bacteria, archaea, plants, yeast and humans. [45]

Splicing and genesis of circRNAs

The existence of backsplicing was first suggested in 2012. [46] This backsplicing explains the genesis of circular RNAs resulting from the exact junction between the 3' boundary of an exon with the 5' boundary of an exon located upstream. [47] In these exonic circular RNAs, the junction is a classic 3'-5'link.

The exclusion of intronic sequences during splicing can also leave traces, in the form of circular RNAs. [48] In some cases, the intronic lariat is not destroyed and the circular part remains as a lariat-derived circRNA [49] .In these lariat-derived circular RNAs, the junction is a 2'-5'link.

See also

Related Research Articles

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">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 code for multiple proteins. In this process, particular exons of a gene may be included within or excluded from the final, processed messenger RNA (mRNA) produced from that gene. This means the exons are joined in different combinations, leading to different (alternative) mRNA strands. Consequently, the proteins translated from alternatively spliced mRNAs usually contain differences in their amino acid sequence and, often, in their biological functions.

<span class="mw-page-title-main">Spliceosome</span> Molecular machine that removes intron RNA from the primary transcript

A spliceosome is a large ribonucleoprotein (RNP) complex found primarily within the nucleus of eukaryotic cells. The spliceosome is assembled from small nuclear RNAs (snRNA) and numerous proteins. Small nuclear RNA (snRNA) molecules bind to specific proteins to form a small nuclear ribonucleoprotein complex, which in turn combines with other snRNPs to form a large ribonucleoprotein complex called a spliceosome. The spliceosome removes introns from a transcribed pre-mRNA, a type of primary transcript. This process is generally referred to as splicing. An analogy is a film editor, who selectively cuts out irrelevant or incorrect material from the initial film and sends the cleaned-up version to the director for the final cut.

<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.

snRNPs, or small nuclear ribonucleoproteins, are RNA-protein complexes that combine with unmodified pre-mRNA and various other proteins to form a spliceosome, a large RNA-protein molecular complex upon which splicing of pre-mRNA occurs. The action of snRNPs is essential to the removal of introns from pre-mRNA, a critical aspect of post-transcriptional modification of RNA, occurring only in the nucleus of eukaryotic cells. Additionally, U7 snRNP is not involved in splicing at all, as U7 snRNP is responsible for processing the 3′ stem-loop of histone pre-mRNA.

Small nuclear RNA (snRNA) is a class of small RNA molecules that are found within the splicing speckles and Cajal bodies of the cell nucleus in eukaryotic cells. The length of an average snRNA is approximately 150 nucleotides. They are transcribed by either RNA polymerase II or RNA polymerase III. Their primary function is in the processing of pre-messenger RNA (hnRNA) in the nucleus. They have also been shown to aid in the regulation of transcription factors or RNA polymerase II, and maintaining the telomeres.

<span class="mw-page-title-main">Minor spliceosome</span>

The minor spliceosome is a ribonucleoprotein complex that catalyses the removal (splicing) of an atypical class of spliceosomal introns (U12-type) from messenger RNAs in some clades of eukaryotes. This process is called noncanonical splicing, as opposed to U2-dependent canonical splicing. U12-type introns represent less than 1% of all introns in human cells. However they are found in genes performing essential cellular functions.

<span class="mw-page-title-main">Group II intron</span> Class of self-catalyzing ribozymes

Group II introns are a large class of self-catalytic ribozymes and mobile genetic elements found within the genes of all three domains of life. Ribozyme activity can occur under high-salt conditions in vitro. However, assistance from proteins is required for in vivo splicing. In contrast to group I introns, intron excision occurs in the absence of GTP and involves the formation of a lariat, with an A-residue branchpoint strongly resembling that found in lariats formed during splicing of nuclear pre-mRNA. It is hypothesized that pre-mRNA splicing may have evolved from group II introns, due to the similar catalytic mechanism as well as the structural similarity of the Group II Domain V substructure to the U6/U2 extended snRNA. Finally, their ability to site-specifically insert into DNA sites has been exploited as a tool for biotechnology. For example, group II introns can be modified to make site-specific genome insertions and deliver cargo DNA such as reporter genes or lox sites

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.

<span class="mw-page-title-main">U11 spliceosomal RNA</span> Non-coding RNA involved in alternative splicing

The U11 snRNA is an important non-coding RNA in the minor spliceosome protein complex, which activates the alternative splicing mechanism. The minor spliceosome is associated with similar protein components as the major spliceosome. It uses U11 snRNA to recognize the 5' splice site while U12 snRNA binds to the branchpoint to recognize the 3' splice site.

<span class="mw-page-title-main">U1 spliceosomal RNA</span>

U1 spliceosomal RNA is the small nuclear RNA (snRNA) component of U1 snRNP, an RNA-protein complex that combines with other snRNPs, unmodified pre-mRNA, and various other proteins to assemble a spliceosome, a large RNA-protein molecular complex upon which splicing of pre-mRNA occurs. Splicing, or the removal of introns, is a major aspect of post-transcriptional modification, and takes place only in the nucleus of eukaryotes.

<span class="mw-page-title-main">U2 spliceosomal RNA</span>

U2 spliceosomal snRNAs are a species of small nuclear RNA (snRNA) molecules found in the major spliceosomal (Sm) machinery of virtually all eukaryotic organisms. In vivo, U2 snRNA along with its associated polypeptides assemble to produce the U2 small nuclear ribonucleoprotein (snRNP), an essential component of the major spliceosomal complex. The major spliceosomal-splicing pathway is occasionally referred to as U2 dependent, based on a class of Sm intron—found in mRNA primary transcripts—that are recognized exclusively by the U2 snRNP during early stages of spliceosomal assembly. In addition to U2 dependent intron recognition, U2 snRNA has been theorized to serve a catalytic role in the chemistry of pre-RNA splicing as well. Similar to ribosomal RNAs (rRNAs), Sm snRNAs must mediate both RNA:RNA and RNA:protein contacts and hence have evolved specialized, highly conserved, primary and secondary structural elements to facilitate these types of interactions.

<span class="mw-page-title-main">U5 spliceosomal RNA</span>

U5 snRNA is a small nuclear RNA (snRNA) that participates in RNA splicing as a component of the spliceosome. It forms the U5 snRNP by associating with several proteins including Prp8 - the largest and most conserved protein in the spliceosome, Brr2 - a helicase required for spliceosome activation, Snu114, and the 7 Sm proteins. U5 snRNA forms a coaxially-stacked series of helices that project into the active site of the spliceosome. Loop 1, which caps this series of helices, forms 4-5 base pairs with the 5'-exon during the two chemical reactions of splicing. This interaction appears to be especially important during step two of splicing, exon ligation.

<span class="mw-page-title-main">U6 spliceosomal RNA</span>

U6 snRNA is the non-coding small nuclear RNA (snRNA) component of U6 snRNP, an RNA-protein complex that combines with other snRNPs, unmodified pre-mRNA, and various other proteins to assemble a spliceosome, a large RNA-protein molecular complex that catalyzes the excision of introns from pre-mRNA. Splicing, or the removal of introns, is a major aspect of post-transcriptional modification and takes place only in the nucleus of eukaryotes.

<span class="mw-page-title-main">U2AF2</span> Protein-coding gene in the species Homo sapiens

Splicing factor U2AF 65 kDa subunit is a protein that in humans is encoded by the U2AF2 gene.

<span class="mw-page-title-main">SmY RNA</span>

SmY ribonucleic acids are a family of small nuclear RNAs found in some species of nematode worms. They are thought to be involved in mRNA trans-splicing.

<span class="mw-page-title-main">Prp24</span>

Prp24 is a protein part of the pre-messenger RNA splicing process and aids the binding of U6 snRNA to U4 snRNA during the formation of spliceosomes. Found in eukaryotes from yeast to E. coli, fungi, and humans, Prp24 was initially discovered to be an important element of RNA splicing in 1989. Mutations in Prp24 were later discovered in 1991 to suppress mutations in U4 that resulted in cold-sensitive strains of yeast, indicating its involvement in the reformation of the U4/U6 duplex after the catalytic steps of splicing.

<span class="mw-page-title-main">Prp8</span>

Prp8 refers to both the Prp8 protein and Prp8 gene. Prp8's name originates from its involvement in pre-mRNA processing. The Prp8 protein is a large, highly conserved, and unique protein that resides in the catalytic core of the spliceosome and has been found to have a central role in molecular rearrangements that occur there. Prp8 protein is a major central component of the catalytic core in the spliceosome, and the spliceosome is responsible for splicing of precursor mRNA that contains introns and exons. Unexpressed introns are removed by the spliceosome complex in order to create a more concise mRNA transcript. Splicing is just one of many different post-transcriptional modifications that mRNA must undergo before translation. Prp8 has also been hypothesized to be a cofactor in RNA catalysis.

<span class="mw-page-title-main">Kiyoshi Nagai</span> Japanese structural biologist (1949–2019)

Kiyoshi Nagai was a Japanese structural biologist at the MRC Laboratory of Molecular Biology Cambridge, UK. He was known for his work on the mechanism of RNA splicing and structures of the spliceosome.

The split gene theory is a theory of the origin of introns, long non-coding sequences in eukaryotic genes between the exons. The theory holds that the randomness of primordial DNA sequences would only permit small (< 600bp) open reading frames (ORFs), and that important intron structures and regulatory sequences are derived from stop codons. In this introns-first framework, the spliceosomal machinery and the nucleus evolved due to the necessity to join these ORFs into larger proteins, and that intronless bacterial genes are less ancestral than the split eukaryotic genes. The theory originated with Periannan Senapathy.

References

  1. ↑ Gilbert W (February 1978). "Why genes in pieces?". Nature. 271 (5645): 501. Bibcode:1978Natur.271..501G. doi: 10.1038/271501a0 . PMID   622185. S2CID   4216649.
  2. ↑ Tonegawa S, Maxam AM, Tizard R, Bernard O, Gilbert W (March 1978). "Sequence of a mouse germ-line gene for a variable region of an immunoglobulin light chain". Proceedings of the National Academy of Sciences of the United States of America. 75 (3): 1485–1489. Bibcode:1978PNAS...75.1485T. doi: 10.1073/pnas.75.3.1485 . PMC   411497 . PMID   418414.
  3. ↑ Tilgner H, Knowles DG, Johnson R, Davis CA, Chakrabortty S, Djebali S, et al. (September 2012). "Deep sequencing of subcellular RNA fractions shows splicing to be predominantly co-transcriptional in the human genome but inefficient for lncRNAs". Genome Research. 22 (9): 1616–1625. doi:10.1101/gr.134445.111. PMC   3431479 . PMID   22955974.
  4. ↑ Roy SW, Gilbert W (March 2006). "The evolution of spliceosomal introns: patterns, puzzles and progress". Nature Reviews. Genetics. 7 (3): 211–221. doi:10.1038/nrg1807. PMID   16485020. S2CID   33672491.
  5. ↑ Clancy S (2008). "RNA Splicing: Introns, Exons and Spliceosome". Nature Education. 1 (1): 31. Archived from the original on 15 March 2011. Retrieved 31 March 2011.
  6. 1 2 Black DL (June 2003). "Mechanisms of alternative pre-messenger RNA splicing". Annual Review of Biochemistry. 72 (1): 291–336. doi:10.1146/annurev.biochem.72.121801.161720. PMID   12626338. S2CID   23576288.
  7. ↑ "Molecular Biology of the Cell". 2012 Journal Citation Reports. Web of Science (Science ed.). Thomson Reuters. 2013.
  8. 1 2 Taggart AJ, DeSimone AM, Shih JS, Filloux ME, Fairbrother WG (June 2012). "Large-scale mapping of branchpoints in human pre-mRNA transcripts in vivo". Nature Structural & Molecular Biology. 19 (7): 719–721. doi:10.1038/nsmb.2327. PMC   3465671 . PMID   22705790.
  9. ↑ Corvelo A, Hallegger M, Smith CW, Eyras E (November 2010). Meyer IM (ed.). "Genome-wide association between branch point properties and alternative splicing". PLOS Computational Biology. 6 (11): e1001016. Bibcode:2010PLSCB...6E1016C. doi: 10.1371/journal.pcbi.1001016 . PMC   2991248 . PMID   21124863.
  10. ↑ Graveley BR, Hertel KJ, Maniatis T (June 2001). "The role of U2AF35 and U2AF65 in enhancer-dependent splicing". RNA. 7 (6): 806–818. doi:10.1017/s1355838201010317. PMC   1370132 . PMID   11421359. Archived from the original on 2018-11-20. Retrieved 2014-12-17.
  11. ↑ Matlin AJ, Clark F, Smith CW (May 2005). "Understanding alternative splicing: towards a cellular code". Nature Reviews. Molecular Cell Biology. 6 (5): 386–398. doi:10.1038/nrm1645. PMID   15956978. S2CID   14883495.
  12. ↑ Matera AG, Wang Z (February 2014). "A day in the life of the spliceosome". Nature Reviews. Molecular Cell Biology. 15 (2): 108–121. doi:10.1038/nrm3742. PMC   4060434 . PMID   24452469.
  13. ↑ Guth S, Valcárcel J (December 2000). "Kinetic role for mammalian SF1/BBP in spliceosome assembly and function after polypyrimidine tract recognition by U2AF". The Journal of Biological Chemistry. 275 (48): 38059–38066. doi: 10.1074/jbc.M001483200 . PMID   10954700.
  14. ↑ Cheng Z, Menees TM (December 2011). "RNA splicing and debranching viewed through analysis of RNA lariats". Molecular Genetics and Genomics. 286 (5–6): 395–410. doi:10.1007/s00438-011-0635-y. PMID   22065066. S2CID   846297.
  15. ↑ Ng B, Yang F, Huston DP, Yan Y, Yang Y, Xiong Z, et al. (December 2004). "Increased noncanonical splicing of autoantigen transcripts provides the structural basis for expression of untolerized epitopes". The Journal of Allergy and Clinical Immunology. 114 (6): 1463–1470. doi:10.1016/j.jaci.2004.09.006. PMC   3902068 . PMID   15577853.
  16. ↑ Patel AA, Steitz JA (December 2003). "Splicing double: insights from the second spliceosome". Nature Reviews. Molecular Cell Biology. 4 (12): 960–970. doi:10.1038/nrm1259. PMID   14685174. S2CID   21816910.
  17. ↑ Sibley CR, Emmett W, Blazquez L, Faro A, Haberman N, Briese M, et al. (May 2015). "Recursive splicing in long vertebrate genes". Nature. 521 (7552): 371–375. Bibcode:2015Natur.521..371S. doi:10.1038/nature14466. PMC   4471124 . PMID   25970246.
  18. ↑ Duff MO, Olson S, Wei X, Garrett SC, Osman A, Bolisetty M, et al. (May 2015). "Genome-wide identification of zero nucleotide recursive splicing in Drosophila". Nature. 521 (7552): 376–379. Bibcode:2015Natur.521..376D. doi:10.1038/nature14475. PMC   4529404 . PMID   25970244.
  19. ↑ Di Segni G, Gastaldi S, Tocchini-Valentini GP (May 2008). "Cis- and trans-splicing of mRNAs mediated by tRNA sequences in eukaryotic cells". Proceedings of the National Academy of Sciences of the United States of America. 105 (19): 6864–6869. Bibcode:2008PNAS..105.6864D. doi: 10.1073/pnas.0800420105 . JSTOR   25461891. PMC   2383978 . PMID   18458335.
  20. ↑ Eul J, Patzel V (November 2013). "Homologous SV40 RNA trans-splicing: a new mechanism for diversification of viral sequences and phenotypes". RNA Biology. 10 (11): 1689–1699. doi:10.4161/rna.26707. PMC   3907479 . PMID   24178438.
  21. ↑ Trotta CR, Miao F, Arn EA, Stevens SW, Ho CK, Rauhut R, Abelson JN (June 1997). "The yeast tRNA splicing endonuclease: a tetrameric enzyme with two active site subunits homologous to the archaeal tRNA endonucleases". Cell. 89 (6): 849–858. doi: 10.1016/S0092-8674(00)80270-6 . PMID   9200603. S2CID   16055381.
  22. ↑ Westaway SK, Phizicky EM, Abelson J (March 1988). "Structure and function of the yeast tRNA ligase gene". The Journal of Biological Chemistry. 263 (7): 3171–3176. doi: 10.1016/S0021-9258(18)69050-7 . PMID   3277966. Archived from the original on 2018-11-18. Retrieved 2014-12-17.
  23. ↑ Paushkin SV, Patel M, Furia BS, Peltz SW, Trotta CR (April 2004). "Identification of a human endonuclease complex reveals a link between tRNA splicing and pre-mRNA 3' end formation". Cell. 117 (3): 311–321. doi: 10.1016/S0092-8674(04)00342-3 . PMID   15109492. S2CID   16049289.
  24. ↑ Soma A (1 April 2014). "Circularly permuted tRNA genes: their expression and implications for their physiological relevance and development". Frontiers in Genetics. 5: 63. doi: 10.3389/fgene.2014.00063 . PMC   3978253 . PMID   24744771.
  25. ↑ Abelson J, Trotta CR, Li H (May 1998). "tRNA splicing". The Journal of Biological Chemistry. 273 (21): 12685–12688. doi: 10.1074/jbc.273.21.12685 . PMID   9582290.
  26. ↑ Fica SM, Tuttle N, Novak T, Li NS, Lu J, Koodathingal P, et al. (November 2013). "RNA catalyses nuclear pre-mRNA splicing". Nature. 503 (7475): 229–234. Bibcode:2013Natur.503..229F. doi:10.1038/nature12734. PMC   4666680 . PMID   24196718.
  27. ↑ Pan Q, Shai O, Lee LJ, Frey BJ, Blencowe BJ (December 2008). "Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing". Nature Genetics. 40 (12): 1413–1415. doi:10.1038/ng.259. PMID   18978789. S2CID   9228930.
  28. ↑ Eksi R, Li HD, Menon R, Wen Y, Omenn GS, Kretzler M, Guan Y (Nov 2013). "Systematically differentiating functions for alternatively spliced isoforms through integrating RNA-seq data". PLOS Computational Biology. 9 (11): e1003314. Bibcode:2013PLSCB...9E3314E. doi: 10.1371/journal.pcbi.1003314 . PMC   3820534 . PMID   24244129.
  29. ↑ Li HD, Menon R, Omenn GS, Guan Y (August 2014). "The emerging era of genomic data integration for analyzing splice isoform function". Trends in Genetics. 30 (8): 340–347. doi:10.1016/j.tig.2014.05.005. PMC   4112133 . PMID   24951248.
  30. ↑ Jain N, Morgan CE, Rife BD, Salemi M, Tolbert BS (January 2016). "Solution Structure of the HIV-1 Intron Splicing Silencer and Its Interactions with the UP1 Domain of Heterogeneous Nuclear Ribonucleoprotein (hnRNP) A1". The Journal of Biological Chemistry. 291 (5): 2331–2344. doi: 10.1074/jbc.M115.674564 . PMC   4732216 . PMID   26607354.
  31. 1 2 Lim KH, Ferraris L, Filloux ME, Raphael BJ, Fairbrother WG (July 2011). "Using positional distribution to identify splicing elements and predict pre-mRNA processing defects in human genes". Proceedings of the National Academy of Sciences of the United States of America. 108 (27): 11093–11098. Bibcode:2011PNAS..10811093H. doi: 10.1073/pnas.1101135108 . PMC   3131313 . PMID   21685335.
  32. ↑ Warf MB, Berglund JA (March 2010). "Role of RNA structure in regulating pre-mRNA splicing". Trends in Biochemical Sciences. 35 (3): 169–178. doi:10.1016/j.tibs.2009.10.004. PMC   2834840 . PMID   19959365.
  33. ↑ Reid DC, Chang BL, Gunderson SI, Alpert L, Thompson WA, Fairbrother WG (December 2009). "Next-generation SELEX identifies sequence and structural determinants of splicing factor binding in human pre-mRNA sequence". RNA. 15 (12): 2385–2397. doi:10.1261/rna.1821809. PMC   2779669 . PMID   19861426.
  34. ↑ Singh PK, Plumb MR, Ferris AL, Iben JR, Wu X, Fadel HJ, et al. (November 2015). "LEDGF/p75 interacts with mRNA splicing factors and targets HIV-1 integration to highly spliced genes". Genes & Development. 29 (21): 2287–2297. doi: 10.1101/gad.267609.115 . PMC   4647561 . PMID   26545813.
  35. 1 2 Shkreta L, Chabot B (October 2015). "The RNA Splicing Response to DNA Damage". Biomolecules. 5 (4): 2935–2977. doi: 10.3390/biom5042935 . PMC   4693264 . PMID   26529031.
  36. ↑ Draper BW, Morcos PA, Kimmel CB (July 2001). "Inhibition of zebrafish fgf8 pre-mRNA splicing with morpholino oligos: a quantifiable method for gene knockdown". Genesis. 30 (3): 154–156. doi: 10.1002/gene.1053 . PMID   11477696. S2CID   32270393.
  37. ↑ Sazani P, Kang SH, Maier MA, Wei C, Dillman J, Summerton J, et al. (October 2001). "Nuclear antisense effects of neutral, anionic and cationic oligonucleotide analogs". Nucleic Acids Research. 29 (19): 3965–3974. doi:10.1093/nar/29.19.3965. PMC   60237 . PMID   11574678.
  38. ↑ Morcos PA (June 2007). "Achieving targeted and quantifiable alteration of mRNA splicing with Morpholino oligos". Biochemical and Biophysical Research Communications. 358 (2): 521–527. doi:10.1016/j.bbrc.2007.04.172. PMID   17493584.
  39. ↑ Bruno IG, Jin W, Cote GJ (October 2004). "Correction of aberrant FGFR1 alternative RNA splicing through targeting of intronic regulatory elements". Human Molecular Genetics. 13 (20): 2409–2420. doi: 10.1093/hmg/ddh272 . PMID   15333583.
  40. ↑ Fu XD, Ares M (October 2014). "Context-dependent control of alternative splicing by RNA-binding proteins". Nature Reviews. Genetics. 15 (10): 689–701. doi:10.1038/nrg3778. PMC   4440546 . PMID   25112293.
  41. ↑ Fu XD, Ares M (October 2014). "Context-dependent control of alternative splicing by RNA-binding proteins". Nature Reviews. Genetics. 15 (10): 689–701. doi:10.1038/nrg3778. PMC   4440546 . PMID   25112293.
  42. ↑ Danckwardt S, Neu-Yilik G, Thermann R, Frede U, Hentze MW, Kulozik AE (March 2002). "Abnormally spliced beta-globin mRNAs: a single point mutation generates transcripts sensitive and insensitive to nonsense-mediated mRNA decay". Blood. 99 (5): 1811–1816. doi: 10.1182/blood.V99.5.1811 . PMID   11861299. S2CID   17128174.
  43. ↑ Ward AJ, Cooper TA (January 2010). "The pathobiology of splicing". The Journal of Pathology. 220 (2): 152–163. doi:10.1002/path.2649. PMC   2855871 . PMID   19918805.
  44. ↑ van Veen H, Vashisht D, Akman M, Girke T, Mustroph A, Reinen E, et al. (October 2016). "Transcriptomes of Eight Arabidopsis thaliana Accessions Reveal Core Conserved, Genotype- and Organ-Specific Responses to Flooding Stress". Plant Physiology. 172 (2): 668–689. doi:10.1104/pp.16.00472. PMC   5047075 . PMID   27208254.
  45. ↑ Hanada K, Yang JC (June 2005). "Novel biochemistry: post-translational protein splicing and other lessons from the school of antigen processing". Journal of Molecular Medicine. 83 (6): 420–428. doi:10.1007/s00109-005-0652-6. PMID   15759099. S2CID   37698110.
  46. ↑ Salzman J, Gawad C, Wang PL, et al. Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS One 2012;7(2):e30733.
  47. ↑ Jeck WR, Sorrentino JA, Wang K, et al. Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA 2013;19(2):141-57.
  48. ↑ Zhang Y, Zhang XO, Chen T, et al. Circular intronic long noncoding RNAs. Molecular cell 2013;51(6):792-806.
  49. ↑ Talhouarne GJ and Gall JG. Lariat intronic RNAs in the cytoplasm of Xenopus tropicalis oocytes. RNA 2014;20(9):1476-87.
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