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From the The average vertebrate gene consists of multiple small exons
(average size, 137 nucleotides) separated by introns that are
considerably larger(1) . Thus, the vertebrate splicing
machinery has the task of finding small desired exons amid much longer
introns. The splice site consensus sequences that drive exon
recognition are located at the very termini of
introns(2, 3) . Despite the discriminatory challenge
faced during exon recognition in large multiexon premessenger RNAs,
vertebrate splice sites are short and poorly conserved. In fact, splice
site sequences in mammals are less conserved than their yeast
counterparts despite the fact that only a minority of genes in Saccharomyces cerevisiae have introns; and those genes that
are split by introns usually have only a single
intron(4, 5) . Thus, vertebrate splicing contends with
a more complex specificity problem via recognition of less precise
consensus sequences. Any mechanism for the orchestration of splicing in
multiexon vertebrate genes must provide an explanation for this puzzle. Part of the solution of the puzzle comes from the observation that
individual splice sites are not independently recognized consensus
sequences. In both yeast and vertebrate splicing, interactions between
5` and 3` splice sites and the factors that recognize them have been
observed during the earliest steps of spliceosome
assembly(4, 5, 6, 7, 8, 9, 10, 11, 12) .
Usually these interactions are depicted as occurring between the 5` and
3` splice sites across an intron. Experimentally, such interactions
have been observed with in vitro splicing precursor RNAs
having naturally short or artificially shortened introns. It is
difficult to extrapolate initial interactions between the factors that
recognize the 5` and 3` splice sites flanking a small vertebrate intron
to introns that can naturally be 100 kilobases in length, especially
given the likelihood that such introns will contain sequences that are
as good a match to consensus splice sites as the actual utilized sites. Models that invoke pairing between the splice sites across an
exon, as contrasted with pairing across an intron, are useful
perspectives of splice site pairing for the splicing of pre-mRNAs with
large introns and small exons. Such an exonic perspective of splice
site recognition has been termed ``exon
definition''(10) . This review discusses exon definition
and contrasts it with intron-oriented perspectives that are more useful
when considering splicing in lower eukaryotes with small introns. The
basic exon definition model proposes that in pre-mRNAs with large
introns, the splicing machinery searches for a pair of closely spaced
splice sites in an exonic polarity (Fig. 1). When such a pair is
encountered, the exon is defined by the binding of U1 and U2 snRNPs (
Figure 1:
Exon Definition in
pre-mRNAs with small exons and large introns. snRNPs (red and green) and SR protein (yellow) are shown interacting
with isolated exons during exon definition. U4/U5/U6 snRNPs (black) are depicted as joining the assembly during the
subsequent step of exon juxtaposition.
Predictions of Exon Definition The exon definition model offers predictions of pre-mRNA
behavior. Several of these predictions have been tested in the last
several years, and the results lend credence to an exonic perspective
of splice site recognition.
Figure 2:
Predictions of the phenotype of mutation
of the 5` splice site bordering an internal exon. Exon pairing of
splice sites predicts exon skipping or the activation of a proximal
cryptic 5` splice site (left), whereas intronic pairing of
splice sites predicts intron inclusion or distal cryptic site
activation (right).
Mutation of vertebrate splice sites
also leads to exon skipping. A survey of mammalian mutations available
in the data base in the summer of 1994 indicated that over 100 splice
site mutations have been characterized in disease gene
DNA(21) . Four phenotypes were observed: exon skipping,
activation of a cryptic splice site, creation of a pseudo-exon within
an intron, and intron retention, in ratios of 51, 32, 11, and 6%,
respectively. The most frequent phenotype was exon skipping. Exon
skipping is a predicted phenotype from an exon perspective because
mutation of the splice site at one side of an exon should inhibit
pairing of splice sites across exons and inhibit recognition of the
exon. Rejection of the exon leads directly to exon skipping. The
observation of exon skipping strongly indicates that splice sites are
recognized as exonic pairs. It is presumably this dependence upon a
pair of sites that minimizes recognition of isolated cryptic sites
within large vertebrate introns. Occasionally, mutation of human genes
has created a strong splice site deep within an intron. Such created
sites have been observed to be utilized via the activation of a nearby
cryptic splice site of the opposite polarity to create a pseudo-exon
from within an intron. Again, the observation is that only pairs of
splice sites can be recognized and that cryptic splices in introns can
only be activated by creation of a nearby site of the opposite type in
an exonic polarity. Occasionally, mutation of an internal splice
site results in intron retention. Exon definition would not predict
intron retention, except perhaps for very small introns. Of the splice
site mutations mentioned above, only 6% caused intron retention. Four
of the included introns were very short, and three were terminal
introns, suggesting abrogation of exon definition modes of recognition
when introns are very small or at the ends of pre-mRNAs (see below).
Three examples involved large internal introns and cannot be explained
by current exon perspectives.
Figure 3:
Internal exon size distribution. Length
distribution of 1600 primate internal exons from a library normalized
to represent highly related exons only a single time (top)
(library kindly provided by D. Searles, University of Pennsylvania) or
194 alternative vertebrate cassette exons (bottom) compiled by
Stamm et al.(46) or by S. Smith and T. A. Cooper
(Baylor College of Medicine).
Last exons begin with a 3` splice site and terminate with a
poly(A) site(30) . They are often the largest exon in a
vertebrate gene, with an average size of approximately 600
nucleotides(1, 31) . Exon recognition predicts that
factors recognizing 3` splice sites interact with factors recognizing
poly(A) sites to recognize last exons. Indeed mutation of 3` splice
sites inhibits the in vitro polyadenylation cleavage
reaction(32) . Just as with first exons, mutation of the signal
at the distal end of a 3-terminal exon, the poly(A) site, inhibits in vitro removal of proximal but not distal
introns(33) . These results suggest that splicing and
polyadenylation factors interact across 3`-terminal exons. The
mechanism of this interaction is unclear, although recent observations
have suggested that U1 snRNPs or the U1 snRNP A protein are involved,
either positively or negatively, via recognition of exon internal
sequences upstream of the polyadenylation signal
AAUAAA(34, 35, 36) .
Exon Enhancer Sequences and Differential Splicing Exon definition has proven to be a useful framework for
considering differential splicing, especially those differential
splicing events involving cassette exons that are differentially
included. Generally, differentially recognized exons have either weaker
splicing signals or a suboptimal length compared with constitutive
exons (3, 37) (Fig. 3), suggesting that the
constitutive exon definition process is so strong as to be difficult to
regulate unless the involved exon recognition signals are weak. Exon
inclusion in these cases appears to be via recognition of special
sequences by tissue or development-specific splicing
factors(38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49) .
One class of sequences commonly found associated with differential
exons, referred to as exon enhancers, resides within the target exon.
The existence of exon internal consensus sequences was initially
surprising because of the constraints imposed upon such sequences by
coding requirements. A family of such sequences, often purine-rich and
coding for a wide variety of amino acids, has been observed to be
important for recognition of weak exons. These sequences appear to be
the binding site for a family of splicing factors known as SR proteins
because of the arginine and serine repeats that characterize
them(50) . In addition to binding exon sequences via their RNA
binding domains, the SR proteins also make protein-protein contacts via
their SR domains with U2AF bound near the 3` splice site and U1 snRNPs
bound to the 5` splice site via arginine-serine-rich domains present in
each(12, 15, 51) . Such recognition makes the
SR proteins ideal candidates for exon-bridging proteins involved in
exon definition. Bridging across exons has been experimentally detected
in that UV cross-linking of U2AF to the 3` splice site of an isolated
exon is affected by the strength of the 5` splice site terminating the
exon(52) . Interestingly, SR proteins have not yet been found in S.
cerevisiae. Even those yeast splicing proteins that are equivalent
in known function to vertebrate proteins containing SR domains lack SR
domains in their yeast forms(53, 54) . From an exon
definition viewpoint, this absence may not be surprising in that
organisms with small introns, such as S. cerevisiae, may not
use exon definition and therefore may not need many or all of the SR
proteins. In general, evidence exists to suggest that pre-mRNAs with
small introns use the intron, rather than the exon, as the initial mode
of pairing between splice sites(4, 5, 11) .
In Saccharomyces pombe, pre-mRNAs have multiple small introns
of less than 100 nucleotides(55) . In Drosophila, 50%
of the introns are less than 100 nucleotides and are often flanked by
large exons(1, 56) . Expanding small introns in either
organism inhibits splicing of the intron or activates cryptic sites
within the expanded introns(57, 58) . ( Mutation of splice sites in genes
with small introns has a different phenotype than the same mutation in
genes with large introns. In pre-mRNAs with small introns, mutation of
an internal 5` splice site does not lead to exon skipping. Instead the
mutated intron is included in the final mRNA and the splicing of
neighboring introns is unaffected (58) . A difference in
splicing signals between the two types of introns has also been
noticed(56, 57) . Small introns often lack the
pyrimidine track located between the branch point and the 3` splice
site of vertebrate but not S. cerevisiae introns. Therefore,
small introns appear to have different signals and to be recognized
somewhat differently than large introns. Initial pairing of splice
sites across an exon may be similar to initial pairing across an
intron. Except for the SR proteins, the vertebrate factors known to be
required for splicing are found in yeast and are required there as
well. Several lines of experimental evidence also suggest that either
the intron or exon can be the pairing unit during pre-mRNA recognition.
As mentioned earlier, expansion of an internal exon in a vertebrate
gene can cause exon skipping. If the same exons and their flanking
splice sites, however, are placed in a gene in which the introns
flanking the expanded exon are small, the expanded exon is
constitutively included(59) .
Figure 4:
Earliest complex formation in vertebrates
via exon definition versus that in lower eukaryotes via intron
definition.
Exon/intron architecture in Drosophilamelanogaster also suggests multiple ways of pairing splice sites within the
same pre-mRNA. Although many Drosophila genes fit neatly into
two categories characterized as genes with small introns and large
exons or as genes with small exons and large introns, there are a
reasonable number of genes that have a mixed exon/intron architecture,
suggesting that over part of their length the exon is the unit of
recognition and over part of their length the intron is the unit of
recognition. Sorting out how two such recognition mechanisms can
operate within the same precursor RNA without a disruption in exon
recognition or exon ordering is one of the future challenges for exon
definition. Although exon definition suggests how exons and their splice
sites are initially recognized by the splicing machinery, it does not
immediately offer a solution to the second step in spliceosome assembly (Fig. 1). Juxtaposition of exons across large vertebrate introns
is a formidable problem, especially if inadvertent exon skipping is to
be avoided. Little insight is available as to how such juxtapositioning
could occur. A likely scenario invokes interactions between the SR
proteins bound to one exon with the SR proteins bound to an adjoining
exon. In addition to the SR proteins, another class of nuclear proteins
found only in organisms with large introns is the hnRNP
proteins(60) . At least one hnRNP protein affects 5` splice
site recognition and is likely to have a major role in differential
splicing (22, 61) . Like the SR proteins, the hnRNP
proteins contain both an RNP recognition domain and a protein-protein
recognition domain. Unlike the SR proteins, the limited information
available suggests that the hnRNP proteins recognize intronic consensus
sequences rather than exonic sequences. Given their capacity to
differentially recognize RNA sequences and their preference for
intronic sequences, the hnRNP proteins remain potential interesting
players in both differential splicing and exon juxtapositioning.
Volume 270,
Number 6,
Issue of February 10, 1995 pp. 2411-2414
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
INTRODUCTION
The Problem
Exon Definition
Predictions of Exon Definition
Exon Enhancer Sequences and Differential Splicing
Intron Definition
Exon Juxtaposition
FOOTNOTES
REFERENCES
)and associated splicing factors, including the 3` splice
site recognizing factors U2AF and SC35 and the 5` splice
site-recognizing factor
ASF/SF2(2, 13, 14, 15, 16) .
Following definition of the exon, neighboring exons must be juxtaposed,
presumably via interactions between the factors that recognize
individual exons. Thus, from this perspective, assembly of the active
vertebrate spliceosome consists of the sequential steps of exon
definition and exon juxtaposition.
Exon Skipping
Exon-oriented and intron-oriented
perspectives of splice site pairing predict different phenotypes
resulting from mutation of splice sites bordering an internal exon (Fig. 2). Models invoking an initial pairing of splice sites
across introns predict that such mutations should inhibit splicing of
the intron in which they occur but should have minimal impact on the
splicing of neighboring introns. In contrast, exon definition predicts
that mutation of a splice site bordering an internal exon should
depress recognition of the exon with concomitant inhibition of splicing
of the adjoining intron, i.e. mutations in an intron will
inhibit the splicing of two introns, the intron containing the mutation
and the intron on the other side of the exon bearing the mutation. This
hypothesis has been tested in vitro, where it was observed
that mutation of a 5` splice site depressed the removal of the upstream
intron 20-fold(17) . The converse experiments have also been
reported. Strengthening a naturally weak 5` splice site of an internal
exon by making it a better fit to the consensus site increased in
vitro splicing of the upstream intron(8, 18) . In vivo, mutant 5` splice sites were genetically suppressed by
second mutations that improved the 3` splice site across the
exon(19, 20) .
Exon Size Maximum
In addition to exon skipping,
the other major phenotype resulting from mutation of a splice site in a
human gene is activation of a cryptic site of the same type. The
activated cryptic site always lies close to the mutated site,
suggesting that splice sites are acceptable only if they reside close
to a site of the opposite polarity and that, therefore, internal
vertebrate exons may have a size maximum imposed in part by the
splicing machinery. Fig. 3indicates the size distribution of
1600 primate internal exons. Of these exons, only 3.5% are longer than
300 nucleotides and less than 1% are longer than 400 nucleotides,
indicating that large internal exons are rare. In vitro, the
assembly of ATP-dependent spliceosomes is inhibited if internal exons
with strong constitutive splice sites are internally expanded to
greater than 300 nucleotides(10) . In vivo, expansion
of internal exons residing in vertebrate genes with moderate to large
introns has two phenotypes: activation of internal cryptic splice sites
within the expanded exon to create small exons or skipping of the
entire exon (see below). (
)These phenotypes are consistent
with splicing-imposed restriction on exon length. Presumably, such a
size limitation helps explain why cryptic splice sites located inside
of long vertebrate introns are not occasionally misrecognized to create
large internal exons when the normal sites are mutated. A few
spectacularly long vertebrate internal exons exit; the mechanism
whereby such exons bypass restrictions on exon length is unknown.
Exon Size Minimum
Simultaneous recognition of
splice sites bordering an exon also suggests that a minimal separation
between the sites might be required to prevent steric hindrance between
the factors that recognize individual sites. When a constitutively
recognized internal exon was internally deleted below 50 nucleotides it
was skipped by the in vivo splicing machinery(23) .
Increasing the strength of the splice sites alleviated problems in
recognition, suggesting that exon size and splice site strength are
additive factors in exon recognition(24) . Some very small
natural internal exons exist. Six and seven nucleotide exons are
frequently found in muscle protein genes; N-CAM has a three-nucleotide
exon. Although few very small exons have been studied, those that have
suggest that very small exons require special enhancing sequences in
addition to strong splice sites for
inclusion(25, 26, 27) . Deletion of these
elements causes exon skipping when the exon is small but not when it
has been internally expanded to a more normal length. The small exon
enhancers are located within the neighboring introns outside of the
normal splice sites. It seems likely that such enhancers function as
binding sites for splicing factors that artificially extend the exon
domain during exon recognition.Terminal Exons
Exon definition suggests that
terminal exons, both first and last exons, will require special
mechanisms for their recognition. First exons end with a 5` splice site
but have no processing signal at their beginning. They do, however,
bear a modification at their beginning via the 7-methylguanosine cap
attached to all polymerase II transcripts. The cap and nuclear proteins
that bind the cap are essential for in vitro splicing of
simple one-intron pre-mRNAs(28) . In two-intron pre-mRNAs,
changing the guanosine cap to an adenosine cap depressed removal of the
first intron in vitro but had only minimal impact on the
second intron (29) . These results indicate both that pre-mRNAs
are recognized segmentally in vitro and that the cap is
essential for recognition and removal of the first intron. Or as stated
from an exon perspective, first exons can be recognized via
interactions between the factors that recognize caps and 5` splice
sites.
)Thus, in genes with small exons, expanding the exon leads
to aberrant splicing, whereas in genes with small introns, expanding
the introns leads to aberrant splicing. These observations suggests
that the pairing unit utilized is that offering the smallest distance
between two adjacent splice sites. Expansion of the
small introns reverts the phenotype to exon skipping. These
observations suggest that large exons are only a problem in genes with
large introns, and more importantly, that the same splice sites can be
recognized in either intronic or exonic polarity (Fig. 4).
)))
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
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I. D'Souza and G. D. Schellenberg Arginine/Serine-rich Protein Interaction Domain-dependent Modulation of a Tau Exon 10 Splicing Enhancer: ALTERED INTERACTIONS AND MECHANISMS FOR FUNCTIONALLY ANTAGONISTIC FTDP-17 MUTATIONS {Delta}280K AND N279K J. Biol. Chem., February 3, 2006; 281(5): 2460 - 2469. [Abstract] [Full Text] [PDF]
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S. LIANG and C. S. LUTZ p54nrb is a component of the snRNP-free U1A (SF-A) complex that promotes pre-mRNA cleavage during polyadenylation. RNA, January 1, 2006; 12(1): 111 - 121. [Abstract] [Full Text] [PDF]
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 M.J. DYE, N. GROMAK, D. HAUSSECKER, S. WEST, and N.J. PROUDFOOT Turnover and Function of Noncoding RNA Polymerase II Transcripts Cold Spring Harb Symp Quant Biol, January 1, 2006; 71(0): 275 - 284. [Abstract] [PDF]
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C. L. ZHENG, X.-D. FU, and M. GRIBSKOV Characteristics and regulatory elements defining constitutive splicing and different modes of alternative splicing in human and mouse RNA, December 1, 2005; 11(12): 1777 - 1787. [Abstract] [Full Text] [PDF]
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K. Yamanegi, S. Tang, and Z.-M. Zheng Kaposi's Sarcoma-Associated Herpesvirus K8{beta} Is Derived from a Spliced Intermediate of K8 Pre-mRNA and Antagonizes K8{alpha} (K-bZIP) To Induce p21 and p53 and Blocks K8{alpha}-CDK2 Interaction J. Virol., November 15, 2005; 79(22): 14207 - 14221. [Abstract] [Full Text] [PDF]
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K. L. Fox-Walsh, Y. Dou, B. J. Lam, S.-p. Hung, P. F. Baldi, and K. J. Hertel The architecture of pre-mRNAs affects mechanisms of splice-site pairing PNAS, November 8, 2005; 102(45): 16176 - 16181. [Abstract] [Full Text] [PDF]
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M. Rush, X. Zhao, and S. Schwartz A Splicing Enhancer in the E4 Coding Region of Human Papillomavirus Type 16 Is Required for Early mRNA Splicing and Polyadenylation as Well as Inhibition of Premature Late Gene Expression J. Virol., September 15, 2005; 79(18): 12002 - 12015. [Abstract] [Full Text] [PDF]
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D. Baek and P. Green Sequence conservation, relative isoform frequencies, and nonsense-mediated decay in evolutionarily conserved alternative splicing PNAS, September 6, 2005; 102(36): 12813 - 12818. [Abstract] [Full Text] [PDF]
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J. Kralovicova, M. B. Christensen, and I. Vorechovsky Biased exon/intron distribution of cryptic and de novo 3' splice sites Nucleic Acids Res., September 1, 2005; 33(15): 4882 - 4898. [Abstract] [Full Text] [PDF]
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H. Lei and I. Vorechovsky Identification of Splicing Silencers and Enhancers in Sense Alus: a Role for Pseudoacceptors in Splice Site Repression Mol. Cell. Biol., August 15, 2005; 25(16): 6912 - 6920. [Abstract] [Full Text] [PDF]
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E. Rosonina, J. Y. Y. Ip, J. A. Calarco, M. A. Bakowski, A. Emili, S. McCracken, P. Tucker, C. J. Ingles, and B. J. Blencowe Role for PSF in Mediating Transcriptional Activator-Dependent Stimulation of Pre-mRNA Processing In Vivo Mol. Cell. Biol., August 1, 2005; 25(15): 6734 - 6746. [Abstract] [Full Text] [PDF]
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 K Ohno, A Tsujino, X-M Shen, M Milone, and A G Engel Spectrum of splicing errors caused by CHRNE mutations affecting introns and intron/exon boundaries J. Med. Genet., August 1, 2005; 42(8): e53 - e53. [Abstract] [Full Text] [PDF]
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 R. Kreutzer, T. Leeb, G. Muller, A. Moritz, and W. Baumgartner A Duplication in the Canine {beta}-Galactosidase Gene GLB1 Causes Exon Skipping and GM1-Gangliosidosis in Alaskan Huskies Genetics, August 1, 2005; 170(4): 1857 - 1861. [Abstract] [Full Text] [PDF]
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X. H-F. Zhang, C. S. Leslie, and L. A. Chasin Dichotomous splicing signals in exon flanks Genome Res., June 1, 2005; 15(6): 768 - 779. [Abstract] [Full Text] [PDF]
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J. M. Burnette, E. Miyamoto-Sato, M. A. Schaub, J. Conklin, and A. J. Lopez Subdivision of Large Introns in Drosophila by Recursive Splicing at Nonexonic Elements Genetics, June 1, 2005; 170(2): 661 - 674. [Abstract] [Full Text] [PDF]
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D. L. Black A simple answer for a splicing conundrum PNAS, April 5, 2005; 102(14): 4927 - 4928. [Full Text] [PDF]
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E. C. Ibrahim, T. D. Schaal, K. J. Hertel, R. Reed, and T. Maniatis From the Cover: Serine/arginine-rich protein-dependent suppression of exon skipping by exonic splicing enhancers PNAS, April 5, 2005; 102(14): 5002 - 5007. [Abstract] [Full Text] [PDF]
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A. B. Osipovich, A. Singh, and H. E. Ruley Post-entrapment genome engineering: First exon size does not affect the expression of fusion transcripts generated by gene entrapment Genome Res., March 1, 2005; 15(3): 428 - 435. [Abstract] [Full Text] [PDF]
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J. Bohne, H. Wodrich, and H.-G. Kräusslich Splicing of human immunodeficiency virus RNA is position-dependent suggesting sequential removal of introns from the 5' end Nucleic Acids Res., February 8, 2005; 33(3): 825 - 837. [Abstract] [Full Text] [PDF]
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 S.-D. Moon, J.-H. Park, E.-M. Kim, J.-H. Kim, J.-H. Han, S.-J. Yoo, K.-H. Yoon, M.-I. Kang, K.-W. Lee, H.-Y. Son, et al. A Novel IVS2-1G>A Mutation Causes Aberrant Splicing of the HRPT2 Gene in a Family with Hyperparathyroidism-Jaw Tumor Syndrome J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 878 - 883. [Abstract] [Full Text] [PDF]
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 N. L. Baker, M. Morgelin, R. Peat, N. Goemans, K. N. North, J. F. Bateman, and S. R. Lamande Dominant collagen VI mutations are a common cause of Ullrich congenital muscular dystrophy Hum. Mol. Genet., January 15, 2005; 14(2): 279 - 293. [Abstract] [Full Text] [PDF]
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 C. J. Webb, C. M. Romfo, W. J. van Heeckeren, and J. A. Wise Exonic splicing enhancers in fission yeast: functional conservation demonstrates an early evolutionary origin Genes & Dev., January 15, 2005; 19(2): 242 - 254. [Abstract] [Full Text] [PDF]
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R. H. Hovhannisyan and R. P. Carstens A Novel Intronic cis Element, ISE/ISS-3, Regulates Rat Fibroblast Growth Factor Receptor 2 Splicing through Activation of an Upstream Exon and Repression of a Downstream Exon Containing a Noncanonical Branch Point Sequence Mol. Cell. Biol., January 1, 2005; 25(1): 250 - 263. [Abstract] [Full Text] [PDF]
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G. Yeo, S. Hoon, B. Venkatesh, and C. B. Burge Variation in sequence and organization of splicing regulatory elements in vertebrate genes PNAS, November 2, 2004; 101(44): 15700 - 15705. [Abstract] [Full Text] [PDF]
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M. G. McPhillips, T. Veerapraditsin, S. A. Cumming, D. Karali, S. G. Milligan, W. Boner, I. M. Morgan, and S. V. Graham SF2/ASF Binds the Human Papillomavirus Type 16 Late RNA Control Element and Is Regulated during Differentiation of Virus-Infected Epithelial Cells J. Virol., October 1, 2004; 78(19): 10598 - 10605. [Abstract] [Full Text] [PDF]
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R. Sorek, R. Shemesh, Y. Cohen, O. Basechess, G. Ast, and R. Shamir A Non-EST-Based Method for Exon-Skipping Prediction Genome Res., August 1, 2004; 14(8): 1617 - 1623. [Abstract] [Full Text] [PDF]
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L. A. Boukis, N. Liu, S. Furuyama, and J. P. Bruzik Ser/Arg-rich Protein-mediated Communication between U1 and U2 Small Nuclear Ribonucleoprotein Particles J. Biol. Chem., July 9, 2004; 279(28): 29647 - 29653. [Abstract] [Full Text] [PDF]
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M. Caputi, M. Freund, S. Kammler, C. Asang, and H. Schaal A Bidirectional SF2/ASF- and SRp40-Dependent Splicing Enhancer Regulates Human Immunodeficiency Virus Type 1 rev, env, vpu, and nef Gene Expression J. Virol., June 15, 2004; 78(12): 6517 - 6526. [Abstract] [Full Text] [PDF]
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 R. C. C. Ryther, A. S. Flynt, B. D. Harris, J. A. Phillips III, and J. G. Patton GH1 Splicing Is Regulated by Multiple Enhancers Whose Mutation Produces a Dominant-Negative GH Isoform That Can Be Degraded by Allele-Specific Small Interfering RNA (siRNA) Endocrinology, June 1, 2004; 145(6): 2988 - 2996. [Abstract] [Full Text] [PDF]
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X. H-F. Zhang and L. A. Chasin Computational definition of sequence motifs governing constitutive exon splicing Genes & Dev., June 1, 2004; 18(11): 1241 - 1250. [Abstract] [Full Text] [PDF]
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P. Stoilov, R. Daoud, O. Nayler, and S. Stamm Human tra2-beta1 autoregulates its protein concentration by influencing alternative splicing of its pre-mRNA Hum. Mol. Genet., March 1, 2004; 13(5): 509 - 524. [Abstract] [Full Text] [PDF]
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X. H-F. Zhang, K. A. Heller, I. Hefter, C. S. Leslie, and L. A. Chasin Sequence Information for the Splicing of Human Pre-mRNA Identified by Support Vector Machine Classification Genome Res., December 1, 2003; 13(12): 2637 - 2650. [Abstract] [Full Text] [PDF]
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S. AWASTHI and J. C. ALWINE Association of polyadenylation cleavage factor I with U1 snRNP RNA, November 1, 2003; 9(11): 1400 - 1409. [Abstract] [Full Text] [PDF]
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H. Gu and D. R. Schoenberg U2AF modulates poly(A) length control by the poly(A)-limiting element Nucleic Acids Res., November 1, 2003; 31(21): 6264 - 6271. [Abstract] [Full Text] [PDF]
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X. Roca, R. Sachidanandam, and A. R. Krainer Intrinsic differences between authentic and cryptic 5' splice sites Nucleic Acids Res., November 1, 2003; 31(21): 6321 - 6333. [Abstract] [Full Text] [PDF]
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S. G. MANSFIELD, R. H. CLARK, M. PUTTARAJU, J. KOLE, J. A. COHN, L. G. MITCHELL, and M. A. GARCIA-BLANCO 5' Exon replacement and repair by spliceosome-mediated RNA trans-splicing RNA, October 1, 2003; 9(10): 1290 - 1297. [Abstract] [Full Text] [PDF]
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M. Rodova, M. R. Islam, K. R. Peterson, and J. P. Calvet Remarkable Sequence Conservation of the Last Intron in the PKD1 Gene Mol. Biol. Evol., October 1, 2003; 20(10): 1669 - 1674. [Abstract] [Full Text]
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K. J. HOWE, C. M. KANE, and M. ARES JR. Perturbation of transcription elongation influences the fidelity of internal exon inclusion in Saccharomyces cerevisiae RNA, August 1, 2003; 9(8): 993 - 1006. [Abstract] [Full Text] [PDF]
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 Y. Zhao, Q. Pan-Hammarstrom, I. Kacskovics, and L. Hammarstrom The Porcine Ig {delta} Gene: Unique Chimeric Splicing of the First Constant Region Domain in its Heavy Chain Transcripts J. Immunol., August 1, 2003; 171(3): 1312 - 1318. [Abstract] [Full Text] [PDF]
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F Gualandi, C Trabanelli, P Rimessi, E Calzolari, L Toffolatti, T Patarnello, G Kunz, F Muntoni, and A Ferlini Multiple exon skipping and RNA circularisation contribute to the severe phenotypic expression of exon 5 dystrophin deletion J. Med. Genet., August 1, 2003; 40(8): e100 - 100. [Full Text] [PDF]
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P. Fortes, Y. Cuevas, F. Guan, P. Liu, S. Pentlicky, S. P. Jung, M. L. Martinez-Chantar, J. Prieto, D. Rowe, and S. I. Gunderson Inhibiting expression of specific genes in mammalian cells with 5' end-mutated U1 small nuclear RNAs targeted to terminal exons of pre-mRNA PNAS, July 8, 2003; 100(14): 8264 - 8269. [Abstract] [Full Text] [PDF]
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B. K. Dredge and R. B. Darnell Nova Regulates GABAA Receptor {gamma}2 Alternative Splicing via a Distal Downstream UCAU-Rich Intronic Splicing Enhancer Mol. Cell. Biol., July 1, 2003; 23(13): 4687 - 4700. [Abstract] [Full Text] [PDF]
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C. G. Miles, L. Rankin, S. I. Smith, M. Niksic, G. Elgar, and N. D. Hastie Faithful expression of a tagged Fugu WT1 protein from a genomic transgene in zebrafish: efficient splicing of pufferfish genes in zebrafish but not mice Nucleic Acids Res., June 1, 2003; 31(11): 2795 - 2802. [Abstract] [Full Text] [PDF]
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N. Volfovsky, B. J. Haas, and S. L. Salzberg Computational Discovery of Internal Micro-Exons Genome Res., June 1, 2003; 13(6): 1216 - 1221. [Abstract] [Full Text] [PDF]
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M. Zavolan, S. Kondo, C. Schonbach, J. Adachi, D. A. Hume, RIKEN GER Group, GSL Members, Y. Hayashizaki, and T. Gaasterland Impact of Alternative Initiation, Splicing, and Termination on the Diversity of the mRNA Transcripts Encoded by the Mouse Transcriptome Genome Res., June 1, 2003; 13(6): 1290 - 1300. [Abstract] [Full Text] [PDF]
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 W. Zhu, S. D. Schlueter, and V. Brendel Refined Annotation of the Arabidopsis Genome by Complete Expressed Sequence Tag Mapping Plant Physiology, June 1, 2003; 132(2): 469 - 484. [Abstract] [Full Text] [PDF]
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C. Y. Yun, A. L. Velazquez-Dones, S. K. Lyman, and X.-D. Fu Phosphorylation-dependent and -independent Nuclear Import of RS Domain-containing Splicing Factors and Regulators J. Biol. Chem., May 9, 2003; 278(20): 18050 - 18055. [Abstract] [Full Text] [PDF]
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 G. Yang, Y.-L. Zhang, G. M. Buchold, A. M. Jetten, and D. A. O'Brien Analysis of Germ Cell Nuclear Factor Transcripts and Protein Expression During Spermatogenesis Biol Reprod, May 1, 2003; 68(5): 1620 - 1630. [Abstract] [Full Text] [PDF]
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M. Lynch and A. Kewalramani Messenger RNA Surveillance and the Evolutionary Proliferation of Introns Mol. Biol. Evol., April 1, 2003; 20(4): 563 - 571. [Abstract] [Full Text] [PDF]
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W. P. Dirksen, S. A. Mohamed, and S. A. Fisher Splicing of a Myosin Phosphatase Targeting Subunit 1 Alternative Exon Is Regulated by Intronic Cis-elements and a Novel Bipartite Exonic Enhancer/Silencer Element J. Biol. Chem., March 7, 2003; 278(11): 9722 - 9732. [Abstract] [Full Text] [PDF]
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N. A. Faustino and T. A. Cooper Pre-mRNA splicing and human disease Genes & Dev., February 15, 2003; 17(4): 419 - 437. [Full Text] [PDF]
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F. Pagani, C. Stuani, E. Zuccato, A. R. Kornblihtt, and F. E. Baralle Promoter Architecture Modulates CFTR Exon 9 Skipping J. Biol. Chem., January 10, 2003; 278(3): 1511 - 1517. [Abstract] [Full Text] [PDF]
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G. Brede, J. Solheim, and H. Prydz PSKH1, a novel splice factor compartment-associated serine kinase Nucleic Acids Res., December 1, 2002; 30(23): 5301 - 5309. [Abstract] [Full Text] [PDF]
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S. E. Ptak and D. A. Petrov How Intron Splicing Affects the Deletion and Insertion Profile in Drosophila melanogaster Genetics, November 1, 2002; 162(3): 1233 - 1244. [Abstract] [Full Text] [PDF]
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 M. R. Carpinelli, I. P. Wicks, N. A. Sims, K. O'Donnell, K. Hanzinikolas, R. Burt, S. J. Foote, M. Bahlo, W. S. Alexander, and D. J. Hilton An Ethyl-Nitrosourea-Induced Point Mutation in Phex Causes Exon Skipping, X-Linked Hypophosphatemia, and Rickets Am. J. Pathol., November 1, 2002; 161(5): 1925 - 1933. [Abstract] [Full Text] [PDF]
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J. Li, D. C. Barnard, and J. G. Patton A Unique Glutamic Acid-Lysine (EK) Domain Acts as a Splicing Inhibitor J. Biol. Chem., October 11, 2002; 277(42): 39485 - 39492. [Abstract] [Full Text] [PDF]
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Y. Aissouni, C. Perez, B. Calmels, and P. D. Benech The Cleavage/Polyadenylation Activity Triggered by a U-rich Motif Sequence Is Differently Required Depending on the Poly(A) Site Location at Either the First or Last 3'-Terminal Exon of the 2'-5' Oligo(A) Synthetase Gene J. Biol. Chem., September 20, 2002; 277(39): 35808 - 35814. [Abstract] [Full Text] [PDF]
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H. Tao, W. Szeszel-Fedorowicz, B. Amir-Ahmady, M. A. Gibson, L. P. Stabile, and L. M. Salati Inhibition of the Splicing of Glucose-6-phosphate Dehydrogenase Precursor mRNA by Polyunsaturated Fatty Acids J. Biol. Chem., August 16, 2002; 277(34): 31270 - 31278. [Abstract] [Full Text] [PDF]
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N. Gromak and C. W. J. Smith A splicing silencer that regulates smooth muscle specific alternative splicing is active in multiple cell types Nucleic Acids Res., August 15, 2002; 30(16): 3548 - 3557. [Abstract] [Full Text] [PDF]
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S. G. Khan, V. Muniz-Medina, T. Shahlavi, C. C. Baker, H. Inui, T. Ueda, S. Emmert, T. D. Schneider, and K. H. Kraemer The human XPC DNA repair gene: arrangement, splice site information content and influence of a single nucleotide polymorphism in a splice acceptor site on alternative splicing and function Nucleic Acids Res., August 15, 2002; 30(16): 3624 - 3631. [Abstract] [Full Text] [PDF]
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 W. G. Fairbrother, R.-F. Yeh, P. A. Sharp, and C. B. Burge Predictive Identification of Exonic Splicing Enhancers in Human Genes Science, August 9, 2002; 297(5583): 1007 - 1013. [Abstract] [Full Text] [PDF]
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