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Coupling transcription, splicing and mRNA export
Robin Reed
Previous studies have led to the view that mRNAs are
transported from the nucleus to the cytoplasm by machinery that
is conserved from yeast to humans. Moreover, this machinery is
coupled both physically and functionally to the pre-mRNA
splicing machinery. During the past year, important new insights
into the mechanisms behind this coupling have been made.
In addition, recent advances have revealed mechanisms for the
co-transcriptional loading of the export machinery on to mRNAs.
Finally, a newly identified link between the nuclear exosome
and the machineries required for transcription, 30 -end formation
and mRNA export suggests that proper mRNP formation is
co-transcriptionally monitored.
Addresses
Department of Cell Biology, 240 Longwood Avenue,
Harvard Medical School, Boston, MA 02115, USA
e-mail: [email protected]
Current Opinion in Cell Biology 2003, 15:326–331
This review comes from a themed issue on
Nucleus and gene expression
Edited by Jeanne Lawrence and Gordon Hager
0955-0674/03/$ – see front matter
ß 2003 Elsevier Science Ltd. All rights reserved.
DOI 10.1016/S0955-0674(03)00048-6
Abbreviations
ChIP
chromatin immunoprecipitation
EJC
exon-junction complex
NPC
nuclear pore complex
RNAi
RNA interference
RNP
ribonucleoprotein
TREX transcription export complex
Introduction
During expression of protein-coding genes, pre-mRNAs
are transcribed in the nucleus and undergo several processing steps, including capping, splicing, 30 -end processing and polyadenylation. The mature mRNA is then
exported through nuclear pore complexes (NPCs) to the
cytoplasm for translation. Although distinct and highly
complex cellular machines carry out each of these steps in
the gene-expression process, growing evidence suggests
the existence of gene-expression factories in which individual machines are functionally coupled. This coupling
is obviously not obligatory, as virtually all of the coupled
steps in gene expression can be uncoupled in various
assays. Thus, coupling probably exists to enable the
proofreading and streamlining of the entire process of
gene expression in vivo. In this review, the discussion will
focus on advances made in the past year in elucidating the
Current Opinion in Cell Biology 2003, 15:326–331
mechanisms coupling splicing and transcription to mRNA
export. In addition, new studies that link the nuclear
exosome to the machineries involved in transcription, 30
end formation and mRNA export will be discussed.
Readers are referred to several recent reviews for more
extensive descriptions of coupling between the different
steps in gene expression [1–7].
Coupling splicing to mRNA export
The notion that splicing is linked to mRNA export first
came from studies in metazoans showing that spliced
mRNAs are assembled into a distinct ‘spliced mRNP’
complex that targets the mRNA for export (for a review,
see [3]). This targeting involves the splicing-dependent
recruitment of the mRNA export factor Aly via its direct
interactions with the spliceosomal protein UAP56. In
Saccharomyces cerevisiae, the counterparts of Aly and
UAP56 also interact with each other directly and are
required for mRNA export. In both S. cerevisiae and
metazoans, Aly also interacts directly with Tap, which,
together with its binding partner p15, associates with the
NPC and is thought to be a general mRNA export
receptor. These and other studies indicate that there is
a conserved machinery for mRNA export, as shown in
Figure 1 (for reviews, see [3,6,8,9]). In metazoans, where
most genes contain introns, this conserved machinery is
intimately tied to the splicing machinery. By contrast, in
S. cerevisiae, where few genes contain introns, it appears
that mRNA export is coupled to other steps in gene
expression.
Work initiated by the Moore group has shown over the
past few years that in metazoans the conserved mRNA
export machinery (UAP/Aly/Tap) and other components
of the spliced mRNP are specifically recruited to a position 20 nucleotides upstream of exon–exon junctions
([10] and references therein). In addition to export
proteins, this exon-junction complex (EJC) contains
several proteins involved in nonsense-mediated decay
(the degradation of mRNAs containing premature stop
codons) and in the cytoplasmic localization of mRNAs.
Thus, the EJC is thought to play multiple roles in mRNA
metabolism. An intriguing feature of the EJC is that it is
positioned on the mRNA at a specific site, but in a
sequence-independent manner. Recently, Moore and
colleagues have begun to determine the mechanism for
positioning the EJC [10]. Their analysis revealed that
numerous proteins (nine were detected) interact with the
50 exon in the catalytically active spliceosome. During
exon ligation, a major restructuring of this region occurs,
placing three other proteins (p170, p95 and p57) at the site
where the EJC forms [10]. Aly and SRp20 (a member of
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Coupling transcription, splicing and mRNA export Reed 327
Figure 1
Mattaj and co-workers [13] addressed the role of splicing in
mRNA export by constructing a hybrid U1 snRNA in
which exons, introns or random sequences were inserted.
The authors concluded that mRNAs contain an ‘identity
element’, which they defined as an unstructured sequence
at least 300 nucleotides long. This identity element is
sufficient to re-direct the hybrid RNA away from the U1
snRNP export pathway and into the UAP/Aly/Tap mRNA
export pathway, even in the absence of splicing. Consistent with previous studies (for a review, see [3]), the
implication of the new work is that splicing is not essential
for export but increases the efficiency and/or fidelity of
the process by promoting the more efficient recruitment
of export factors.
Spliceosome
UAP
ALY UAP
Spliced
mRNP
ALY
TAP
Nucleus
Cytoplasm
Current Opinion in Cell Biology
Conserved mRNA export machinery coupled to splicing. UAP56 (Sub2 in
yeast), which is present in the spliceosome, recruits Aly (Yra1 in yeast) to
the mRNA during splicing. UAP56 is replaced by the mRNA export
receptor TAP/p15 (Mex67/MTR2 in yeast).
the SR protein family of splicing factors) also contact this
region in the EJC [10]. These five RNA-contacting
proteins are therefore likely to play key roles in EJC
formation. Once formed, the EJC is associated with
mRNAs that are bound in the nucleus by the cap-binding
protein CBP80 but not with mRNAs bound by the
cytoplasmic eIF4E cap-binding protein [11]. The EJC
proteins associate with CBP80-bound mRNAs both in the
nucleus and in the cytoplasm, suggesting that the entire
EJC is exported and then dissociates from the mRNA in
the cytoplasm [11]. In yeast, Lei and Silver [12] used the
chromatin immunoprecipitation (ChIP) method to show
that Yra1 (yeast Aly) and Sub2 (yeast UAP56) associate
preferentially with the intron region, in a splicing-dependent manner. Thus, it is possible that both splicingdependent recruitment of the mRNA export machinery
and EJC formation are also conserved.
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In an unexpected twist to the emerging story of the
conserved mRNA export pathway and the EJC, a new
Drosophila RNA interference (RNAi) study by Gatfield
and Izaurralde [14] concludes that, although both Tap
and UAP56 are required for mRNA export, Aly and the
other EJC components are dispensable. The authors
propose that an as-yet undiscovered adaptor protein(s)
must exist that mediates the interaction between Tap and
the mRNA. However, there are alternative possibilities;
the RNAi-mediated knockdown of Aly and the other EJC
proteins may not have been sufficient to eliminate their
functions, or there may be a redundancy in factors.
Indeed, the new conclusion is difficult to reconcile with
previous work. For example, antibodies to Aly block
mRNA export, and recombinant Aly stimulates mRNA
export (for a review, see [3]). Moreover, the physical and
functional conservation of UAP, Aly, and Tap from yeast
to humans implicates these proteins as key players in
mRNA export [3,8].
Coupling transcription to mRNA export
Although the UAP/Aly/Tap pathway is conserved from
yeast to humans, the export machinery is not solely
recruited by a splicing-dependent mechanism. Indeed,
95% of S. cerevisiae genes as well as several metazoan
genes lack introns. Nevertheless, in both metazoans and
yeast, the conserved UAP/Aly/Tap pathway is required
for the export of mRNAs derived from genes lacking
introns ([14] and references therein). Thus, a central focus
of recent work has been to determine the mechanisms for
splicing-independent recruitment of this machinery. In
earlier work, the Silver group shed light on this problem
by providing evidence that the mRNA export machinery
is co-transcriptionally recruited in S. cerevisiae (for a
review, see [6]). During the past year, new advances have
been made that support this view and that identify
possible mechanisms for the recruitment.
In one recent study in S. cerevisiae, Strasser et al. [15]
showed that Sub2 and Yra1 specifically associate with the
multisubunit THO complex, which is thought to be
involved in transcription elongation (for a review, see
Current Opinion in Cell Biology 2003, 15:326–331
328 Nucleus and gene expression
[16]). Null mutants in any of the non-essential THO
complex subunits (Hpr1, Tho2, Mtf1 and Thp2) also
display an unusually high level of transcription-dependent recombination ([16,17] and references therein). This
hyper-recombination phenotype may be a secondary consequence of the polymerase elongation defect, which
exposes transcription units to recombination [16]. In the
study by Strasser et al. [15], all four subunits of the THO
complex were found to interact genetically and physically
with bothYra1 and Sub2. In addition, the THO-complex
null mutants are defective in mRNA export. Finally, ChIP
assays revealed that THO complex components, as well as
Yra1 and Sub2, associate with actively transcribed genes
[15,18]. The THO complex together with the mRNA
export proteins is designated the transcription export complex (TREX) [15]. Together, the data support a model in
which the TREX complex plays a role in coupling transcription to mRNA export. Stutz and co-workers [18]
have advanced this model further by showing that the
THO/TREX component Hpr1 interacts directly with
Sub2 and plays a role in recruiting Sub2 and Yra1 to actively
transcribed genes.
In another study in S. cerevisiae, Hurt and co-workers [19]
identified what are likely to be new components of the
conserved mRNA export machinery, with links to the
transcription machinery. Performing a synthetic lethal
screen with Yra1 (yeast Aly), they identified the Sac3
gene. The Sac3 protein was also identified by mass
spectrometry by virtue of its association with Sub2 (yeast
UAP56) in a pull-down assay from yeast lysates [15].
Sac3 was also shown to interact directly with Mex67
(yeast Tap). Thus, Sac3 interacts physically and functionally with all of the components of the UAP/Aly/TAP
pathway. But the story does not end there; Sac3 also forms
a complex with Thp1, a protein thought to function in
transcription elongation, and Hurt and coworkers [19]
showed that both Sac3 and Thp1 are required for mRNA
export. Moreover, Sac3 also interacts with two nucleoporins (Nup 60 and Nup 1) that are located on the
nucleocytoplasmic face of the NPC and that are required
for mRNA export. On the basis of these observations,
Hurt and coworkers proposed a model in which Sac3 first
associates with the mRNP early in its formation, perhaps
during transcription, and then, by interacting with both
Mex67 and the two nucleoporins, facilitates docking of
the mRNP at the nuclear-pore complex.
Silver’s group [20] also identified Sac3 in a synthetic
lethal screen using a known mRNA export factor, in this
case MTR2 (the small subunit of the Mex67/MTR2
mRNA export receptor [Tap/p15 in metazoans]). Sac3
was shown to function in mRNA export, to interact
genetically with several mRNA export factors and to
associate physically with Mex67, MTR2 and specific
nuclear-pore-complex-associated proteins involved in
mRNA export. Immunolocalization of Sac3 revealed
Current Opinion in Cell Biology 2003, 15:326–331
that it associates with the cytoplasmic fibrils of the
NPC. Significantly, when Sac3 is mutated, Mex67 accumulates at the nuclear rim [20]. On the basis of these
results, Silver and co-workers [20] propose that Sac3
plays a role in a terminal step in the process whereby
Mex67 is translocated across the NPC. Considering both
the Hurt and Silver studies, it is possible that Sac3
associates with the mRNA during transcription, plays
a role in docking Mex67 to the nuclear pore and then
functions in the translocation of Mex67 across the
nuclear pore. Metazoan counterparts of Sac3 and
Thp1 have been identified. Thus, it would not be
surprising if these proteins play a role in mRNA export
in metazoans.
Links between mRNA export and other
steps in gene expression
Surprising new studies by the Jensen group [21] and the
Stutz group [18] have linked the TREX complex to the
nuclear exosome, a large complex of 30 to 50 exonucleases
involved in numerous RNA processing and degradation
pathways. The two new studies have shown genetic
interactions between exosome and TREX complex components. Moreover, Yra1 interacts physically with the
exosomal protein Rrp45 [18]. Previous studies have
shown that TREX complex mutants generate transcripts
that are truncated at their 30 ends (for a review, see [16]).
Jensen and colleagues have now shown that in these
mutants, as well as in mutants that affect proper 30 end
formation, mRNAs are rapidly sequestered near their
sites of transcription ([21] and references therein). Both
this phenotype and the 30 -end truncation phenotype can
be rescued by deletion of the exosome component Rrp6
[21]. Together, these studies led to the view that proper
mRNP formation is monitored by the exosome, resulting
in retention and destruction of aberrant mRNPs at their
sites of transcription [7,18,21].
Significantly, another link was recently made between
the exosome and transcription elongation factors (Spt5
and Spt6) [22]. In this study, Lis and co-workers showed
that the exosome physically associates with Spt5 and Spt6
and is recruited to actively transcribed genes, possibly by
these proteins. Together, the new data suggest a model
for how the exosome, the TREX complex, Spt5 and Spt6
regulate transcription elongation, mRNP formation and
export. In this model, Spt5 and Spt6 recruit the exosome
to RNA polymerase II at an early stage of transcription
(Figure 2). The TREX complex, which associates with
the gene at a later stage of transcription, may physically
protect the mRNP from the exosome or may even function as an exosome inhibitor (Figure 2a). When the
TREX complex is missing (as in the TREX-null
mutants), the 30 ! 50 exonuclease activity of the exosome
destroys the growing mRNP, leading to the dissociation
of RNA polymerase from DNA and thus blocking transcription elongation (Figure 2b). When both the TREX
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Coupling transcription, splicing and mRNA export Reed 329
Figure 2
Exosome
Spt5,6
RNAP II
5′
(a)
TREX
Exosome
ALY
Spt5,6
UAP
RNAP II
(b)
3′
Exosome
S
Spt5,6
RNAP II
(c)
Spt5,6
RNAP II
5′
ALY
UAP
Exported
3′ truncated/degraded
Full length
Not exported
Not exported
Current Opinion in Cell Biology
In this model, coupling the transcription and export machineries to the exosome enables the monitoring of proper mRNP formation. The exosome is
recruited during transcription, possibly by the elongation factors Spt5 and Spt6. When the TREX complex is present, a proper mRNP is made
containing export proteins (Aly and UAP56) and the mRNA is exported (a). In the absence of the TREX complex, the exosome degrades the mRNA
from the 30 to the 50 end and the transcription machinery dissociates (b). When both the TREX complex and the exosome are absent, transcription can
occur but the mRNP lacks export proteins and is not exported (c).
complex and the exosome are missing, full-length transcripts would be generated but not exported because the
export machinery cannot be recruited (Figure 2c). Thus,
the purpose of coupling the exosome to the TREX
complex is to ensure that any transcripts that lack the
TREX complex, and hence the mRNA export machinery,
are targeted for destruction.
Although ample evidence indicates that the mRNA
export machinery is co-transcriptionally loaded onto
mRNAs in yeast, 30 -end formation may play a more
critical role in this loading. For example, Lei and Silver
[12] find that Sub2 is not required for the recruitment of
Yra1 to genes that lack introns. However, proper 30 -end
formation is required to recruit this factor, whether or not
an intron is present. This observation supports earlier
studies indicating that 30 -end formation is important for
mRNA export (for reviews, see [6,7]). In further support
of this view, Rosbash’s group has recently reported that
transcripts generated by T7 polymerase (i.e. not by RNA
polymerase II) are exported only if 30 -end formation
occurs normally [23]. This story has also been extended
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by Hammel et al. [24]. In a screen to identify genes
required for mRNA export, several factors involved in
termination and 30 processing were obtained. The study
also showed that the deletion of sequences in the mRNA
that are involved in coupling termination and 30 end
formation leads to the synthesis of transcripts that cannot
be exported. Thus, the authors propose that termination,
30 processing and mRNA export are all coupled.
Coupling transcription and splicing to
mRNA export in metazoans
Numerous recent studies in metazoans have provided
compelling new evidence that transcription can affect
splicing and vice versa (see for example [25–28]). Because
of space restrictions, the discussion here will be limited to
recent advances concerning the coupling of both transcription and splicing to mRNA export. In particular,
Strasser et al. [15] identified the likely counterpart of
the TREX complex in mammals. As in yeast, this complex contains mRNA export proteins (Aly and UAP56) as
well as THO complex components (hTho2 and hHpr1).
It is not yet known whether this putative mammalian
Current Opinion in Cell Biology 2003, 15:326–331
330 Nucleus and gene expression
Acknowledgements
Figure 3
I am grateful to Ming-Juan Luo, Ed Hurt and Tom Maniatis for helpful
comments on the review and to Claudine Christoforides for assistance in
preparation of the manuscript. I apologize for references that were not cited
because of space limitations.
References and recommended reading
ALY UAP
Spliceosome
Papers of particular interest, published within the annual period of
review, have been highlighted as:
of special interest
of outstanding interest
ALY UAP
1.
Orphanides G, Reinberg D: A unified theory of gene expression.
Cell 2002, 108:439-451.
2.
Bentley D: The mRNA assembly line: transcription and
processing machines in the same factory. Curr Opin Cell Biol
2002, 14:336-342.
3.
Reed R, Hurt E: A conserved mRNA export machinery coupled
to pre-mRNA splicing. Cell 2002, 108:523-531.
4.
Maniatis T, Reed R: An extensive network of coupling among
gene expression machines. Nature 2002, 416:499-506.
5.
Proudfoot NJ, Furger A, Dye MJ: Integrating mRNA processing
with transcription. Cell 2002, 108:501-512.
6.
Lei EP, Silver PA: Protein and RNA export from the nucleus.
Dev Cell 2002, 2:261-272.
7.
Jensen TH, Rosbash M: Co-transcriptional monitoring of mRNP
formation. Nat Struct Biol 2003, 10:10-12.
8.
Izaurralde E: A novel family of nuclear transport receptors
mediates the export of messenger RNA to the cytoplasm.
Eur J Cell Biol 2002, 81:577-584.
9.
Dreyfuss G, Kim VN, Kataoka N: Messenger-RNA-binding
proteins and the messages they carry. Nat Rev Mol Cell Biol
2002, 3:195-205.
TREX
RNAP II
Current Opinion in Cell Biology
In this model, coupling transcription, splicing and export via the TREX
complex targets the export machinery to exons. Metazoan introns
are typically very large whereas the exons are minute. The TREX
complex may associate with the spliceosome to allow co-transcriptional
loading of the export machinery (Aly and UAP56) onto exons, which are
destined for export, and to exclude this machinery from the introns,
which are retained in the nucleus.
TREX complex associates with the nascent pre-mRNA
during transcription. Surprisingly, however, all of the
mammalian TREX complex components were found in
purified spliceosomes [29–32]. Thus, the TREX complex
may function to link both transcription and splicing to
mRNA export in metazoans. One model that may explain
why the TREX complex is linked to splicing in metazoans concerns the structure of their genes. In metazoans,
the abundant introns are typically thousands to tens of
thousands of nucleotides in length and can be as large as
several hundred thousand nucleotides. The exons, averaging only 100 nucleotides, are minute by comparison.
Thus, as shown in Figure 3, the TREX complex may be
associated with the spliceosome as a mechanism for cotranscriptionally targeting the mRNA export factors only
to exons, which are destined for export, and not to the
numerous enormous introns, which are retained and
degraded in the nucleus.
Conclusions
Recent studies strengthen the view that mRNA export is
coupled to other steps in gene expression including
splicing, transcription, and 30 -end formation. In addition,
new links between mRNA export, transcription and the
nuclear exosome were revealed. Future directions will
include a detailed characterization of the spliced mRNP
and EJC that couples splicing to mRNA export. In addition, the role of the TREX complex in export and
transcription, and the relationship between these processes and the nuclear exosome remain to be determined.
Finally, the molecular basis for coupling 30 -end formation
to mRNA export must be identified.
Current Opinion in Cell Biology 2003, 15:326–331
10. Reichert VL, Le Hir H, Jurica MS, Moore MJ: 50 exon interactions
within the human spliceosome establish a framework for exon
junction complex structure and assembly. Genes Dev 2002,
16:2778-2791.
The authors explored formation of the EJC. The data show that a set of
proteins contacts the exon during splicing and that extensive remodeling
then occurs in this region as the exon junction is formed.
11. Lejeune F, Ishigaki Y, Li X, Maquat LE: The exon junction complex
is detected on CBP80-bound but not eIF4E-bound mRNA in
mammalian cells: dynamics of mRNP remodeling.
EMBO J 2002, 21:3536-3545.
12. Lei EP, Silver PA: Intron status and 30 -end formation control
cotranscriptional export of mRNA. Genes Dev 2002,
16:2761-2766.
13. Ohno M, Segref A, Kuersten S, Mattaj IW: Identity elements used
in export of mRNAs. Mol Cell 2002, 9:659-671.
14. Gatfield D, Izaurralde E: REF1/Aly and the additional exon
junction complex proteins are dispensable for nuclear mRNA
export. J Cell Biol 2002, 159:579-588.
15. Strasser K, Masuda S, Mason P, Pfannstiel J, Oppizzi M,
Rodriguez-Navarro S, Rondon AG, Aguilera A, Struhl K, Reed R
et al.: TREX is a conserved complex coupling transcription with
messenger RNA export. Nature 2002, 417:304-308.
A new complex containing mRNA export factors and transcription factors
is identified in yeast and mammals. The complex may function in the
co-transcriptional loading of mRNA export factors.
16. Jimeno S, Rondon AG, Luna R, Aguilera A: The yeast THO
complex and mRNA export factors link RNA metabolism
with transcription and genome instability. EMBO J 2002,
21:3526-3535.
17. Aguilera A: The connection between transcription and genomic
instability. EMBO J 2002, 21:195-201.
18. Zenklusen D, Vinciguerra P, Wyss JC, Stutz F: Stable mRNP
formation and export require cotranscriptional recruitment of
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Coupling transcription, splicing and mRNA export Reed 331
the mRNA export factors Yra1p and Sub2p by Hpr1p.
Mol Cell Biol 2002, 22:8241-8253.
This study shows that the THO/TREX complex component Hpr1 interacts
with the mRNA export factor Sub2 and plays a role in recruiting Sub2 to
the mRNA during transcription. The study also shows links between the
TREX complex and the nuclear exosome, suggesting that proper mRNP
formation is co-transcriptionally monitored.
19. Fischer T, Strasser K, Racz A, Rodriguez-Navarro S, Oppizzi M,
Ihrig P, Lechner J, Hurt E: The mRNA export machinery
requires the novel Sac3p-Thp1p complex to dock at the
nucleoplasmic entrance of the nuclear pores. EMBO J 2002,
21:5843-5852.
Sac3 is identified as a new mRNA export factor. Sac3 was shown to
interact with specific proteins, leading to the proposal that Sac3 is loaded
onto mRNA co-transcriptionally and later functions to dock the mRNP at
the nuclear pore.
20. Lei EP, Stern CA, Fahrenkrog B, Krebber H, Moy TI, Aebi U,
Silver PA: Sac3 is an mRNA export factor that localizes to the
cytoplasmic fibrils of the nuclear pore complex. Mol Biol Cell
2002, 14:836-847.
This study also identifies Sac3 as a new mRNA export factor. The authors
show that Sac3 localizes to the cytoplasmic fibrils and may play a role in a
terminal step of mRNP translocation.
21. Libri D, Dower K, Boulay J, Thomsen R, Rosbash M, Jensen TH:
Interactions between mRNA export commitment, 30 -end
quality control, and nuclear degradation. Mol Cell Biol 2002,
22:8254-8266.
This study reports a link between the TREX complex and the nuclear
exosome, providing further evidence for the author’s proposal that the
exosome monitors proper mRNP formation co-transcriptionally.
22. Andrulis ED, Werner J, Nazarian A, Erdjument-Bromage H,
Tempst P, Lis JT: The RNA processing exosome is linked to
elongating RNA polymerase II in Drosophila. Nature 2002,
420:837-841.
This study is the first to show that the nuclear exosome is recruited to
actively transcribed genes. The elongation factors Spt5 and Spt6 are in a
complex with the exosome and may play a role in recruiting it to active
genes. The study further strengthens the notion that proper mRNP
formation is monitored during transcription.
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23. Dower K, Rosbash M: T7 RNA polymerase-directed transcripts
are processed in yeast and link 30 end formation to mRNA
nuclear export. RNA 2002, 8:686-697.
This study shows that 30 -end formation plays a key role in mRNA export in
yeast.
24. Hammell CM, Gross S, Zenklusen D, Heath CV, Stutz F, Moore C,
Cole CN: Coupling of termination, 30 processing, and mRNA
export. Mol Cell Biol 2002, 22:6441-6457.
These authors report that termination and 30 end processing are coupled
to mRNA export in yeast.
25. Kwek KY, Murphy S, Furger A, Thomas B, O’Gorman W, Kimura H,
Proudfoot NJ, Akoulitchev A: U1 snRNA associates with TFIIH
and regulates transcriptional initiation. Nat Struct Biol 2002,
9:800-805.
26. Auboeuf D, Honig A, Berget SM, O’Malley BW: Coordinate
regulation of transcription and splicing by steroid receptor
coregulators. Science 2002, 298:416-419.
27. Furger A, O’Sullivan JM, Binnie A, Lee BA, Proudfoot NJ: Promoter
proximal splice sites enhance transcription. Genes Dev 2002,
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28. Kadener S, Fededa JP, Rosbash M, Kornblihtt AR: Regulation of
alternative splicing by a transcriptional enhancer through RNA
pol II elongation. Proc Natl Acad Sci USA 2002, 99:8185-8190.
29. Jurica MS, Licklider LJ, Gygi SR, Grigorieff N, Moore MJ: Purification
and characterization of native spliceosomes suitable for
three-dimensional structural analysis. RNA 2002, 8:426-439.
30. Hartmuth K, Urlaub H, Vornlocher HP, Will CL, Gentzel M, Wilm M,
Luhrmann R: Protein composition of human prespliceosomes
isolated by a tobramycin affinity-selection method.
Proc Natl Acad Sci USA 2002, 99:16719-16724.
31. Zhou Z, Licklider LJ, Gygi SP, Reed R: Comprehensive proteomic
analysis of the human spliceosome. Nature 2002, 419:182-185.
32. Rappsilber J, Ryder U, Lamond AI, Mann M: Large-scale
proteomic analysis of the human spliceosome. Genome Res
2002, 12:1231-1245.
Current Opinion in Cell Biology 2003, 15:326–331