Origin of Spliceosomal Introns and Alternative Splicing

Irimia, Manuel; Roy, Scott William

doi:10.1101/cshperspect.a016071

Cited by 130 publications

(134 citation statements)

References 225 publications

(271 reference statements)

Supporting

Mentioning

124

Contrasting

Unclassified

Order By: Relevance

“…Although how the spliceosomal introns emerged and why only eukaryotes possess this class of introns remain unclear, it is widely accepted that the spliceosomal introns originated from the group II self-splicing introns and appeared at the time of eukaryogenesis (11,18). It is likely that the proto-spliceosomal introns resembled the group II introns and for some period retained their mobility and self-splicing ability (5).…”

Section: Discussionmentioning

confidence: 99%

“…S2). Indeed, at this time in evolution, budding yeast is a species in which widespread intron loss has been proposed to have occurred, likely through RNA-mediated homologous recombination of cDNA (9,11). This model is likely to be correct, as it reflects the genomic reality that budding yeast introns generally exist close to the 5′ end of intron-containing genes, as would be expected in a reaction mediated by reverse transcriptase, which begins copying the mRNA from the 3′ end (7,(12)(13)(14).…”

mentioning

confidence: 99%

“…Definitive conclusions of intron gain or loss are difficult to make by these analyses, however it is clear that introns massively infiltrated the genome of the last eukaryotic common ancestor and that introns have continued to be gained and lost over evolutionary time (11,18).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Spliceosomal intronogenesis

Stevens¹

2016

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

View full text Add to dashboard Cite

The presence of intervening sequences, termed introns, is a defining characteristic of eukaryotic nuclear genomes. Once transcribed into pre-mRNA, these introns must be removed within the spliceosome before export of the processed mRNA to the cytoplasm, where it is translated into protein. Although intron loss has been demonstrated experimentally, several mysteries remain regarding the origin and propagation of introns. Indeed, documented evidence of gain of an intron has only been suggested by phylogenetic analyses. We report the use of a strategy that detects selected intron gain and loss events. We have experimentally verified, to our knowledge, the first demonstrations of intron transposition in any organism. From our screen, we detected two separate intron gain events characterized by the perfect transposition of a reporter intron into the yeast genes RPL8B and ADH2, respectively. We show that the newly acquired introns are able to be removed from their respective pre-mRNAs by the spliceosome. Additionally, the novel allele, RPL8Bint, is functional when overexpressed within the genome in a strain lacking the Rpl8 paralogue RPL8A, demonstrating that the gene targeted for intronogenesis is functional.ne of the defining features of all eukaryotic organisms is the presence of intervening sequences termed introns in at least some nuclear genes (1, 2). The removal of introns from eukaryotic pre-mRNA within the spliceosome is mechanistically related to self-cleaving group II introns from prokaryotes and eukaryotic organelles (3-5) (Fig. S1). Although much work has been done in examining the mechanism and machinery of spliceosomal intron removal (1, 2), several evolutionary mysteries remain regarding introns: How did spliceosomal introns invade and persist in eukaryotic genomes? How are they removed from the genomes of organisms undergoing intron loss? Have introns been added over evolutionary time, and if so, how does that occur?Several models exist for how introns might be lost (6-8), and experimental intron loss has been demonstrated in at least one organism (9, 10) ( Fig. S2). Indeed, at this time in evolution, budding yeast is a species in which widespread intron loss has been proposed to have occurred, likely through RNA-mediated homologous recombination of cDNA (9, 11). This model is likely to be correct, as it reflects the genomic reality that budding yeast introns generally exist close to the 5′ end of intron-containing genes, as would be expected in a reaction mediated by reverse transcriptase, which begins copying the mRNA from the 3′ end (7,(12)(13)(14).Models for how introns are gained are numerous, however no model has yet been experimentally validated (15, 16). These models include intron transposition, intron gain during double-stranded DNA break repair, transfer of an intron from a paralogous gene, and an appealing model involving reverse-splicing. This model invokes the incorporation of an intron retained in the residual spliceosome into an intron-naïve mRNA that has encountered and stably interac...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Spliceosomal intronogenesis

Stevens¹

2016

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

View full text Add to dashboard Cite

show abstract

“…RNA splicing, the process from nuclear pre-mRNA into mature mRNA where introns are excised and the exons (coding regions) are joined together is mediated by a large complex, called spliceosome or spliceosomal machinery (32,33). In human genome, 60% of the mature mRNAs are spliced by alternative splicing in which pre-mRNAs can be spliced in more than one way (34,35).…”

Section: The Spliceosomal Machinery and Rna Splicing Regulationmentioning

confidence: 99%

Aberrant RNA splicing and mutations in spliceosome complex in acute myeloid leukemia

Zhou

Chng

2017

Stem Cell Investig.

View full text Add to dashboard Cite

The spliceosome, the cellular splicing machinery, regulates RNA splicing of messenger RNA precursors (pre-mRNAs) into maturation of protein coding RNAs. Recurrent mutations and copy number changes in genes encoding spliceosomal proteins and splicing regulatory factors have tumor promoting or suppressive functions in hematological malignancies, as well as some other cancers. Leukemia stem cell (LSC) populations, although rare, are essential contributors of treatment failure and relapse. Recent researches have provided the compelling evidence that link the erratic spicing activity to the LSC phenotype in acute myeloid leukemia (AML). In this article, we describe the diverse roles of aberrant splicing in hematological malignancies, particularly in AML and their contributions to the characteristics of LSC. We review these promising strategies to exploit the addiction of aberrant spliceosomal machinery for anti-leukemic therapy with aim to eradicate LSC. However, given the complexity and plasticity of spliceosome and not fully known functions of splicing in cancer, the challenges facing the development of the therapeutic strategies targeting RAN splicing are highlighted and future directions are discussed too.

show abstract

“…A favored scenario for the origin of a eukaryotic cell is endosymbiosis, based on an archaeon hosting a bacterial invader that carried group II introns and evolved into mitochondria (124,125,203,204,205). Although this scenario remains a matter of debate particularly among those who favor bacterial-archaeal fusion scenarios for the origin of eukaryotes (206,207,208), the bacterial species thought to have evolved into mitochondria and chloroplasts, α-proteobacteria and cyanobacteria, respectively, both harbor copious numbers of group II introns (209).…”

Section: Role Of Group II Introns In the Origin Of Eukaryotesmentioning

confidence: 99%

Mobile Bacterial Group II Introns at the Crux of Eukaryotic Evolution

2015

View full text Add to dashboard Cite

This review focuses on recent developments in our understanding of group II intron function, the relationships of these introns to retrotransposons and spliceosomes, and how their common features have informed thinking about bacterial group II introns as key elements in eukaryotic evolution. Reverse transcriptase-mediated and host factor-aided intron retrohoming pathways are considered along with retrotransposition mechanisms to novel sites in bacteria, where group II introns are thought to have originated. DNA target recognition and movement by target-primed reverse transcription infer an evolutionary relationship among group II introns, non-LTR retrotransposons, such as LINE elements, and telomerase. Additionally, group II introns are almost certainly the progenitors of spliceosomal introns. Their profound similarities include splicing chemistry extending to RNA catalysis, reaction stereochemistry, and the position of two divalent metals that perform catalysis at the RNA active site. There are also sequence and structural similarities between group II introns and the spliceosome's small nuclear RNAs (snRNAs) and between a highly conserved core spliceosomal protein Prp8 and a group II intron-like reverse transcriptase. It has been proposed that group II introns entered eukaryotes during bacterial endosymbiosis or bacterial-archaeal fusion, proliferated within the nuclear genome, necessitating evolution of the nuclear envelope, and fragmented giving rise to spliceosomal introns. Thus, these bacterial self-splicing mobile elements have fundamentally impacted the composition of extant eukaryotic genomes, including the human genome, most of which is derived from close relatives of mobile group II introns.

show abstract

Origin of Spliceosomal Introns and Alternative Splicing

Cited by 130 publications

References 225 publications

Spliceosomal intronogenesis

Spliceosomal intronogenesis

Aberrant RNA splicing and mutations in spliceosome complex in acute myeloid leukemia

Mobile Bacterial Group II Introns at the Crux of Eukaryotic Evolution

Contact Info

Product

Resources

About