An unexpected ending: Noncanonical 39 end processing
JEREMY E. WILUSZ1and DAVID L. SPECTOR2
1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
2Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA
Proper 39 end processing of a nascent transcript is critical for the functionality of the mature RNA. Although it has long been
thought that virtually all long RNA polymerase II transcripts terminate in a poly(A) tail that is generated by endonucleolytic
cleavage followed by polyadenylation, noncanonical 39 end processing mechanisms have recently been identified at several
gene loci. Unexpectedly, enzymes with well-characterized roles in other RNA processing events, such as tRNA biogenesis and
pre-mRNA splicing, cleave these nascent transcripts to generate their mature 39 ends despite the presence of nearby
polyadenylation signals. In fact, the presence of multiple potential 39 end cleavage sites is the norm at many human genes,
and recent work suggests that the choice among sites is regulated during development and in response to cellular cues. It is,
therefore, becoming increasing clear that the selection of a proper 39 end cleavage site represents an important step in the
regulation of gene expression and that the mature 39 ends of RNA polymerase II transcripts can be generated via multiple
Keywords: polyadenylation; post-transcriptional regulation of gene expression; RNA splicing; tRNA biogenesis; RNA process-
ing; RNA polymerase II
39 End processing of a nascent transcript is critical for
allowing the release of RNA polymerase from its template
and for ensuring the proper functionality of the mature
RNA. By varying the 39 end cleavage site, additional
sequence motifs are included (or excluded) at the 39 end
of the mature RNA, which can, for example, affect the
transcript’s stability or subcellular localization (for review,
see Moore 2005). In addition, the choice of an alternative
39 end processing site can result in a mature messenger
RNA that encodes a protein with very different domains
and function, as exemplified by the immunoglobulin M
(IgM) heavy chain gene locus, where the choice between 39
end cleavage sites determines if the mature RNA encodes
a protein that is secreted or localized to the membrane
(Takagaki et al. 1996). As there are two or more functional
polyadenylation signals at more than half of all human
genes (Tian et al. 2005; Yan and Marr 2005), the selection
of each 39 end cleavage site must be tightly regulated. In
fact, mutations in polyadenylation signals or in 39 end
processing factors have been linked to numerous human
diseases, including cancer and thalassemia, highlighting the
impact that inappropriate 39 end formation can have on
human health (for review, see Danckwardt et al. 2008).
It has long been thought that the mature 39 end of nearly
all long RNA polymerase II transcripts, besides many his-
tone mRNAs, is generated in a two-step reaction that
involves endonucleolytic cleavage followed by the addition
of adenosine (A) residues in a nontemplated fashion.
However, large-scale studies of the human transcriptome
now indicate that transcription is pervasive throughout the
human genome (for review, see Kapranov et al. 2007;
Wilusz et al. 2009) and suggest that a significant fraction
(>25%) of long transcripts present in cells lack a classical
poly(A) tail (Cheng et al. 2005; Wu et al. 2008), indicating
that additional 39 end processing mechanisms likely exist in
vivo. In this review, we discuss the known mechanisms by
which the mature 39 ends of long RNA polymerase II (Pol
II) transcripts are generated. Canonical cleavage/polyade-
nylation and histone 39 end formation are only briefly
addressed as these mechanisms have been thoroughly
reviewed elsewhere (Colgan and Manley 1997; Zhao et al.
Reprint requests to: David L. Spector, Cold Spring Harbor Laboratory,
1 Bungtown Road, Cold Spring Harbor, NY 11724, USA; e-mail: spector@
cshl.edu; fax: (516) 367-8876.
Article published online ahead of print. Article and publication date are
RNA (2010), 16:259–266. Published by Cold Spring Harbor Laboratory Press. Copyright ? 2010 RNA Society.
1999; Proudfoot 2004; Marzluff et al. 2008). Instead, we
focus on two recently identified 39 end processing mech-
anisms that use enzymes with well-characterized roles in
other RNA processing events. As there are often multiple
potential cleavage sites at the 39 ends of human genes, we
then highlight recent genome-wide studies that have begun
to reveal how the choice of a 39 end cleavage site is
systematically regulated and the effects that this has on
the fate of the mature transcripts.
A poly(A) tail is thought to be added post-transcriptionally
to the 39 end of almost all eukaryotic mRNAs, which
influences the transcript’s stability, translational efficiency,
and export to the cytoplasm (for review, see Colgan and
Manley 1997; Zhao et al. 1999; Proudfoot 2004). Core
polyadenylation sequence elements present in nascent
transcripts, including the hexanucleotide AAUAAA (or
a close variant) and a downstream G/U-rich sequence,
recruit the cleavage/polyadenylation machinery, resulting
in endonucleolytic cleavage of the RNA by CPSF-73
(Mandel et al. 2006). A poly(A) tail (up to 200–250
adenosines in mammalian cells) is then added by poly(A)
polymerase in a nontemplated fashion to the 39 end of the
transcript. Interestingly, the length of the poly(A) tail can
be regulated to control translation of the mRNA, as
exemplified by the regulation of many maternal mRNAs
in developing oocytes (for review, see Richter 1999).
Although the mechanism by which a poly(A) tail is
added seems fairly simple, proteomic analysis has revealed
that the human cleavage/polyadenylation complex may be
composed of up to z85 proteins (Shi et al. 2009). In-
terestingly, many of these protein components may not
play a direct role in 39 end formation, but instead function
to closely couple cleavage/polyadenylation to multiple
other cellular processes, including transcription, especially
transcriptional termination, and pre-mRNA splicing (for
review, see Shatkin and Manley 2000; Maniatis and Reed
2002; Proudfoot et al. 2002; Bentley 2005; Richard and
Manley 2009). Coupling aids in maximizing the efficiency
of each step in gene expression and likely contributes to the
specificity of poly(A) site choice. In particular, some
transcripts have, in addition to the core polyadenylation
sequence elements, auxiliary sequence motifs located up-
stream of or downstream from the cleavage site, which
affect the usage of the nearby poly(A) site by binding
various accessory proteins (Lutz 2008, and references
Unexpectedly, several recent reports indicate that pro-
teins other than CPSF-73 can generate the 39 end of an
mRNA prior to polyadenylation. For example, at the yeast
CTH2 locus, co-transcriptional cleavage at the poly(A)
signal does not normally occur, resulting in a readthrough
transcript that extends z1.8 kilobases (kb) beyond the
poly(A) signal (Ciais et al. 2008). However, this primary
transcript is then progressively degraded by the 39-59
exonuclease activity of the nuclear exosome/TRAMP com-
plex until the complex pauses at a G/U-rich sequence,
allowing post-transcriptional polyadenylation and produc-
tion of the mature polyadenylated mRNA. The RNase III
type endonuclease Rnt1 has also now been shown in yeast
to be able to cleave and generate the 39 end of some
mRNAs, which are subsequently polyadenylated (Rondo ´n
et al. 2009).
HISTONE AND snRNA 39 END FORMATION
Although nearly all mRNAs are thought to have a poly(A)
tail at their 39 end, it is not an absolute rule. It has long
been known that the mature 39 end of replication-de-
pendent histone mRNAs is generated by U7 snRNA base
pairing to a highly conserved element known as the histone
downstream element (HDE), followed by endonucleolytic
cleavage but no polyadenylation (for review, see Marzluff
et al. 2008). Instead of having a poly(A) tail, histone
mRNAs have a highly conserved stem–loop structure in
their 39 UTRs that binds the stem–loop binding protein
(SLBP) and is functionally analogous to a poly(A) tail as it
ensures RNA stability and enhances translational efficiency.
Interestingly, despite the obvious mechanistic differences
between canonical cleavage/polyadenylation and histone 39
end formation, CPSF-73 is the endonuclease involved in
both mechanisms (Dominski et al. 2005; Mandel et al.
In addition to protein-coding mRNAs, RNA polymerase
II transcribes numerous small noncoding RNAs, including
the majority of snRNAs (small nuclear RNAs), which also
lack a poly(A) tail at their 39 ends. At these snRNA loci,
phosphorylation of serine 7 of the carboxy-terminal do-
main (CTD) of RNA polymerase II recruits a complex of at
least 12 proteins known as the Integrator, which mediates
39 end processing of snRNAs near the 39 box sequence
(Baillat et al. 2005; Egloff et al. 2007). Perhaps not
surprisingly, two of the Integrator subunits are similar to
the subunits of the cleavage and polyadenylation specificity
factor (CPSF) complex (Baillat et al. 2005).
RNase P GENERATES THE MATURE 39 END OF TWO
LONG NONCODING RNAS
In its well-characterized role, RNase P endonucleolytically
cleaves tRNA precursors to produce the mature 59 termini
of functional tRNAs (for review, see Kirsebom 2007).
Importantly, it does this by structural, not sequence-de-
pendent, recognition of tRNAs, allowing RNase P to
recognize similar features present in other RNA transcripts.
For example, RNase P has been shown to cleave the
Saccharomyces cerevisiae noncoding RNA HRA1 (Yang
and Altman 2007) and several bacterial riboswitches (Altman
Wilusz and Spector
RNA, Vol. 16, No. 2
et al. 2005), as well as been proposed to cleave several
intron-encoded box C/D small nucleolar RNAs (snoRNAs)
as part of their maturation process in yeast (Coughlin et al.
2008). A connection between RNase P and 39 end forma-
tion of mRNAs has long been known in mitochondria,
where tRNAs generally flank protein-coding sequences in
the mitochondrial genome (Ojala et al. 1981). Unexpect-
edly, we recently showed that RNase P also generates the
39 ends of two long RNA polymerase II transcripts, MALAT1
and MEN b (Wilusz et al. 2008; Sunwoo et al. 2009).
MALAT1 (metastasis-associated lung adenocarcinoma
transcript 1), also known as NEAT2 (Hutchinson et al.
2007), is a long noncoding RNA that is misregulated in
many cancers (Ji et al. 2003; Lin et al. 2007) and specifically
retained in the nucleus in nuclear speckles (Hutchinson
et al. 2007), domains that are thought to be involved in the
assembly, modification, and/or storage of the pre-mRNA
processing machinery (for review, see Lamond and Spector
2003). At the 39 end of the MALAT1 locus is a cleavage/
polyadenylation signal, which can be used to generate a
polyadenylated MALAT1 transcript that is z7 kb in mouse
(z7.4 kb in human). Unexpectedly, we found this poly-
adenylated isoform of MALAT1 to be a very minor isoform
in vivo (<1% of the MALAT1 transcripts present in the cell).
Instead, the mature 39 end of MALAT1 is almost always
generated several hundred nucleotides upstream of the
poly(A) site at a region that folds into a tRNA-like struc-
ture (Fig. 1A; Wilusz et al. 2008). This upstream region is
the most highly evolutionarily conserved portion of the
MALAT1 locus (with conservation extending to stickleback)
and, like canonical tRNAs, folds into a cloverleaf secondary
structure. RNase P recognizes the tRNA-like structure and
cleaves to simultaneously generate the mature 39 end of the
abundant MALAT1 transcript and the 59 end of a small 61-
nucleotide (nt) tRNA-like transcript. Additional enzymes
involved in tRNA biogenesis, including RNase Z and the
CCA-adding enzyme, further process the small RNA, which
we have named mascRNA (MALAT1-associated small cyto-
plasmic RNA), prior to its export to the cytoplasm (Wilusz
et al. 2008). Therefore, by using RNase P to generate the
mature 39 end of MALAT1, the cell is able to process a single
nascent transcript into two mature transcripts that localize
to distinct subcellular locations and likely have unique
Despite the 39 end of MALAT1 being generated via
a mechanism very distinct from canonical cleavage/poly-
adenylation, the mature MALAT1 transcript still has a short
(<20 nt) poly(A)-rich tract on its 39 end (Wilusz et al.
2008). Interestingly, rather than being added on post-
transcriptionally, as occurs during polyadenylation, the
MALAT1 poly(A) tail-like moiety is actually encoded in
the genome and thus part of the nascent transcript (Fig.
1B). RNase P simply cleaves immediately downstream from
the A-rich motif (Fig. 1A), providing a twist on how
a poly(A) tract can be generated on the 39 end of a mature
Pol II transcript. Considering the short length of the A-rich
motif and the fact that it is interrupted by nucleotides other
than A, it is perhaps not too surprising that there are
additional sequence motifs that stabilize the 39 end of
MALAT1. Upstream of the A-rich motif are two highly
conserved U-rich motifs that are predicted to be able to
base pair with the poly(A) tail-like moiety (Fig. 1B).
Indeed, when we mutated these U-rich motifs to disrupt
the base pairing, MALAT1 was deadenylated in vitro,
implicating these upstream motifs in stabilizing the
MALAT1 transcript (Wilusz et al. 2008). Short upstream
U-rich motifs have been shown to stabilize other transcripts
by interacting with their poly(A) tails (Muhlrad and Parker
2005; Conrad et al. 2006, 2007), suggesting that this
mechanism may be more common than we currently
appreciate. In addition, it is tempting to speculate that
there are additional transcripts with genomically encoded
poly(A) tail-like moieties at their 39 ends.
Upon searching the mouse and human genomes for
sequences similar to the 39 end of MALAT1, we found that
MEN b, a >20-kb noncoding RNA that is, curiously, also
retained in the nucleus, is processed at its 39 end via a very
similar mechanism involving RNase P (Sunwoo et al.
2009). In contrast to MALAT1, which localizes to nuclear
speckles, MEN b serves as a key structural component of
paraspeckles (Sasaki et al. 2009; Sunwoo et al. 2009).
Considering that both MALAT1 and MEN b are nuclear
retained, a simple model could be envisioned in which
39 end processing of a long RNA polymerase II transcript
by RNase P is a signal to retain the transcript in the
nucleus. However, the MALAT1 and MEN b loci both
make additional RNA isoforms whose 39 ends are generated
by the canonical cleavage/polyadenylation mechanism and
are retained in the nucleus (Wilusz et al. 2008; Sunwoo
et al. 2009). Therefore, instead of RNase P cleavage serving
as the nuclear retention signal, there are likely sequence
motifs within the transcripts that designate them for
nuclear retention, perhaps via specific protein interactions.
It should be noted that a number of other long nuclear-
retained noncoding RNAs, such as Xist (Memili et al.
2001), Hsr-omega-n (Hogan et al. 1994), Airn (Seidl et al.
2006), and Kcnq1ot1 (Redrup et al. 2009), are also poly-
adenylated, indicating that not all polyadenylated tran-
scripts are exported to the cytoplasm.
THE SPLICEOSOME GENERATES THE MATURE
39 END OF SCHIZOSACCHAROMYCES POMBE
The complete replication of telomeric DNA at the ends of
eukaryotic chromosomes requires telomerase, a ribonucleo-
protein complex that copies a short template sequence
within its intrinsic RNA moiety onto chromosome ends
(for review, see Blackburn 2005). In S. pombe, although
there is a poly(A) site at the 39 end of the telomerase RNA
Noncanonical 39 end processing mechanisms
(TER1) locus, 95% of the TER1 RNA in the cell ends
upstream of this site and is not polyadenylated (Fig. 2;
Leonardi et al. 2008; Webb and Zakian 2008). In fact, the
longer polyadenylated TER1 isoforms are inactive in vivo as
they fail to form a complex with the catalytic protein
subunit of telomerase (Box et al. 2008; Leonardi et al.
2008), emphasizing the significance of proper 39 end site
choice for the generation of a functional transcript. How
then is the 39 end of the shorter, functional S. pombe
telomerase RNA transcript generated? Recent work in-
dicates that the answer, unexpectedly, is the spliceosome
as the mature 39 end of TER1 precisely maps to a 59 splice
site (Box et al. 2008).
In its well-characterized role, the spliceosome removes
each noncoding intron from pre-messenger RNAs via two
transesterification reactions to generate mature messenger
RNAs that can be translated (for review, see Wahl et al.
2009). In the first step of RNA splicing, the phosphodiester
FIGURE 1. MALAT1 is processed at its 39 end by the tRNA processing machinery. (A) Although there is a canonical polyadenylation signal at the
39 end of the mouse MALAT1 locus, MALAT1 is primarily processed via an upstream cleavage mechanism, which yields a mature z6.7-kb
transcript with a short poly(A) tail-like moiety at its 39 end (Wilusz et al. 2008). Endonucleolytic cleavage by RNase P simultaneously generates
the mature 39 end of MALAT1 and the 59 end of mascRNA. The small RNA is subsequently cleaved by RNase Z and subjected to CCA addition to
generate the mature 61-nt tRNA-like transcript. (B) The MALAT1 poly(A) tail-like moiety (shaded in blue) is highly conserved and encoded in
the genome. Further upstream are two nearly perfectly conserved U-rich motifs (shaded in green and orange) separated by a conserved predicted
Wilusz and Spector
RNA, Vol. 16, No. 2
bond at the 59 splice site is attacked by the 29 hydroxyl of an
adenosine at the branch point in the intron, forming the
lariat intermediate. The 39 hydroxyl of the free 59 exon then
attacks the phosphodiester bond at the 39 splice site,
resulting in ligation of the exons and excision of the lariat
intron. These two steps of RNA splicing are tightly coupled
to prevent the release of intermediates and ensure that the
exons are properly joined.
However, at the S. pombe TER1 locus, these two splicing
steps become uncoupled and only the first transesterifica-
tion reaction occurs, resulting in the release of the 59 exon
(corresponding to the active TER1 RNA) without exon
ligation (Fig. 2; Box et al. 2008). Supporting this model,
mutations in the 59 splice site or the branch point, which
affect the first step of splicing, were found to cause a stark
decrease in the levels of mature active TER1 RNA and
resulted in telomere shortening. In contrast, mutating the
39 splice site, which only affects the second step in splicing,
had no effect on mature TER1 levels or telomere length.
Therefore, in a single-step reaction, the spliceosome can
generate the mature 39 end of TER1 RNA in S. pombe (Box
et al. 2008) and likely other yeast species
(Gunisova et al. 2009). Curiously, if
both splicing steps are completed, the
resulting TER1 transcript is not active,
likely because it is rapidly degraded
(Fig. 2). Exactly how the first and sec-
ond steps of splicing become uncoupled
is still a mystery, although the presence
of suboptimal splicing motifs in the
TER1 transcript appears to play a role.
As with the MALAT1 locus, the ma-
ture 39 end of the S. pombe TER1 tran-
script is nearly exclusively generated by
a noncanonical 39 end processing mech-
anism, despite the presence of a down-
stream poly(A) site. It is possible that
these transcripts may be polyadenylated
prior to the upstream noncanonical
cleavage event, but further experiments
are needed to clarify this point and de-
termine if sequential 39 end cleavage
reactions occur or if the noncanonical
cleavage event can occur in the absence
of downstream polyadenylation. Never-
theless, although there are currently
only a handful of known genetic loci
that use these noncanonical mechanisms,
it is important to specifically point out
that they are the rule, rather than the
exception, for how the mature 39 ends of
these particular RNAs are generated. In
addition, as these noncanonical 39 end
processing mechanisms use enzymes with
well-established roles in other RNA pro-
cessing events, they underscore the previously suggested idea
that all of the various RNA processing pathways are inter-
connected (Shatkin and Manley 2000; Maniatis and Reed
2002; Proudfoot et al. 2002) and provide additional connec-
tions that were unexpected.
POST-TRANSCRIPTIONAL CLEAVAGE OF AN mRNA
TO ALLOW TRAFFICKING TO THE CYTOPLASM
Although 39 end formation is generally thought to occur
co-transcriptionally (Bentley 2005), some nuclear-retained
transcripts are cleaved post-transcriptionally to generate
a shorter mRNA isoform that is subsequently exported to
the cytoplasm and translated. For example, CTN-RNA is
transcribed from the protein-coding mouse cationic amino
acid transporter 2 (mCAT2) locus, but the use of a distal
poly(A) site causes the z8-kb transcript to have a long
39 UTR that is subjected to RNA editing, resulting in
nuclear retention of the transcript (Prasanth et al. 2005).
When cells are later subjected to stress, CTN-RNA is
somehow post-transcriptionally cleaved in its 39 UTR to
FIGURE 2. Incomplete splicing generates the functional S. pombe TER1 transcript. A short
intron, with canonical 59 and 39 splice sites (denoted 59 ss and 39 ss, respectively) and branch
point sequences, is located upstream of a canonical polyadenylation signal at the 39 end of the
S. pombe TER1 locus. Although the two transesterification steps of splicing are normally tightly
coupled, they somehow become uncoupled at the TER1 locus such that only the first step is
normally completed. The 59 exon is released and subsequently functions as the active RNA
component of telomerase (Box et al. 2008). If both splicing steps are completed or if the
mature 39 end of TER1 is generated by cleavage/polyadenylation, the resulting TER1 transcripts
are inactive and fail to support telomere maintenance.
Noncanonical 39 end processing mechanisms
generate a z4.2-kb transcript that can traffic to the cy-
toplasm to be translated. As RNA editing has been observed
in the 39 UTRs of many genes (Kim et al. 2004; Levanon
et al. 2004; Chen et al. 2008), it is perhaps not too
surprising that a similar regulatory mechanism appears to
be employed at the migration stimulating factor (MSF)
gene locus (Kay et al. 2005) and proposed to occur at many
other genes (Chen et al. 2008). However, the molecular
mechanism of this post-transcriptional cleavage process is
unclear, as neither the enzymes responsible nor the exact
RNA cleavage sites are known. In one possible model, post-
transcriptional cleavage would simply generate a new
mature 39 end on the shorter transcript (which may or
may not be subsequently polyadenylated). However, a re-
cent bioinformatics study has suggested the intriguing
possibility that CTN-RNA and other edited transcripts
instead may undergo a noncanonical splicing mechanism
that removes the edited region (Osenberg et al. 2009). The
resulting noncanonically spliced transcript thus would lack
the sequence elements responsible for nuclear retention,
but maintain the same mature 39 end as the precursor
transcript. Further experiments are required to distinguish
between these potential mechanisms and determine the
extent that alternative poly(A) site usage combined with
RNA editing and post-transcriptional cleavage is used to
regulate protein expression.
THE SELECTION OF 39 END CLEAVAGE SITES
IS REGULATED DURING DEVELOPMENT
Although we are only beginning to appreciate the extent to
which noncanonical 39 end processing mechanisms are
used throughout the genome, it will be of considerable
interest to determine how the various 39 end processing
machineries are selectively recruited and used to generate
the proper mature 39 end of each Pol II transcript.
Currently, the most is known about alternative polyadeny-
lation, as it has been estimated that more than half of all
human genes have the choice between two or more 39 end
cleavage sites (Tian et al. 2005; Lutz 2008). Many of these
alternative polyadenylation signals are evolutionarily con-
served (Ara et al. 2006; Lee et al. 2007) and their use
systematically changes during development (Zhang et al.
2005; Liu et al. 2007; Ji et al. 2009). Interestingly, upstream
poly(A) sites are preferentially used in rapidly proliferating
cells, especially in cancer cells, resulting in mRNAs with
shorter 39 UTRs (Sandberg et al. 2008; Mayr and Bartel
2009). In some cases, these mRNAs with truncated 39 UTRs
have increased stability or are translated more efficiently
due to the lack of microRNA binding sites, showing that
even relatively subtle changes to the mRNA caused by
alternative poly(A) site usage, such as a change in the
length of the 39 UTR, can have drastic effects on gene
expression. In contrast, as mouse embryonic development
progresses, downstream poly(A) sites are preferentially
used, resulting in mRNAs with longer 39 UTRs, likely
increasing the post-transcriptional regulation of these
transcripts (Ji et al. 2009).
How then is the choice between different 39 end cleavage
sites regulated? Although we do not yet know how non-
canonical 39 end processing mechanisms are selected over
canonical cleavage/polyadenylation sites, patterns of alter-
native splicing and alternative cleavage/polyadenylation are
strongly correlated, suggesting that splicing and 39 end site
selection are likely regulated in a coordinated manner
(Wang et al. 2008). Interestingly, recent reports suggest
that nucleosome positioning (Spies et al. 2009), as well as
epigenetic modifications, namely DNA methylation, may
play a role in 39 end site selection (Wood et al. 2008).
Additionally, neuronal activity has been shown to affect
poly(A) site selection at many genes and a short motif was
found to be enriched near these activity-regulated poly(A)
sites (Flavell et al. 2008). Considering the importance of
39 end site selection for the fate of the mature transcript, it
is likely that we are only beginning to appreciate how the
choice of sites is regulated.
SUMMARY AND PERSPECTIVES
Although canonical cleavage/polyadenylation is the mech-
anism by which the mature 39 end of many, if not the vast
majority, of long RNA polymerase II transcripts is gener-
ated, recent studies have uncovered several gene loci that
use other endonucleases, including RNase P and the
spliceosome, to cleave the nascent transcript. Interestingly,
at the MALAT1 and S. pombe TER1 loci, despite the
presence of nearby poly(A) sites, mechanisms other than
canonical cleavage/polyadenylation are nearly exclusively
employed to generate the mature 39 end of the transcripts.
It is not yet clear how broadly these noncanonical 39 end
processing mechanisms are used throughout the genome,
but the complexity of the transcriptome and the presence
of many long transcripts that lack a poly(A) tail (Cheng
et al. 2005; Wu et al. 2008) suggest that they may be much
more common than we currently appreciate.
J.E.W. was supported by a Beckman Graduate Studentship while
at the Watson School of Biological Sciences. Research in the
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