A CTD function linking transcription to splicing

Corden, Jeffry L.; Patturajan, Meera

doi:10.1016/s0968-0004(97)01125-0

Cited by 146 publications

(112 citation statements)

References 34 publications

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“…Human cyclin L2 possesses RS-repeat domains, a characteristic feature of SR protein/spliceosome components, and associates and co-localizes with the known splicing factors SC-35 and 9G8. RS domains have been discovered in several factors associated with transcription components, including the SR-like CTD-associated factors (33) and in a 3Ј-end cleavage factor, cleavage factor-I 68-kDa subunit (34), suggesting that communication between splicing and both transcription and 3Ј-end processing might in some cases be mediated by interactions involving RS domain proteins (35,36). We have confirmed the stimulatory effect of cyclin L2 in pre-mRNA splicing.…”

Section: Discussionsupporting

confidence: 76%

Cyclin L2, a Novel RNA Polymerase II-associated Cyclin, Is Involved in Pre-mRNA Splicing and Induces Apoptosis of Human Hepatocellular Carcinoma Cells

Yang¹,

Li²,

Wang

et al. 2004

Journal of Biological Chemistry

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We report the cloning and functional characterization of human cyclin L2, a novel member of the cyclin family. Human cyclin L2 shares significant homology to cyclin L1, K, T1, T2, and C, which are involved in transcriptional regulation via phosphorylation of the C-terminal domain of RNA polymerase II. The cyclin L2 protein contains an N-terminal ''cyclin box'' and C-terminal dipeptide repeats of alternating arginines and serines, a hallmark of the SR family of splicing factors. A new isoform and the mouse homologue of human cyclin L2 have also been cloned in this study. Human cyclin L2 is expressed ubiquitously in normal human tissues and tumor cells. We show here that cyclin L2 co-localizes with splicing factors SC-35 and 9G8 within nuclear speckles and that it associates with hyperphosphorylated, but not hypophosphorylated, RNA polymerase II and CDK p110 PITSLRE kinase via its N-terminal cyclin domains. It can also associate with the SC-35 and 9G8 through its RS repeat region. Recombinant cyclin L2 protein can stimulate in vitro mRNA splicing. Overexpression of human cyclin L2 suppresses the growth of human hepatocellular carcinoma SMMC 7721 cells both in vitro and in vivo, inducing cellular apoptosis. This process involves up-regulation of p53 and Bax and decreased expression of Bcl-2. The data suggest that cyclin L2 represents a new member of the cyclin family, which might regulate the transcription and RNA processing of certain apoptosis-related factors, resulting in tumor cell growth inhibition and apoptosis.Cyclins are key regulatory proteins that complex with and activate cyclin-dependent kinase (CDK) 1 subunits (1-4), playing pivotal roles in the regulation of cell cycle progression (5).Cyclins may be currently classified into two major groups, seemingly reflecting their functions. The cell cycle regulator cyclins, composed primarily of cyclin A, B, D1, D2, D3, E, and F, function with their CDK partners including CDK1, -2, -3, and -4 to regulate promotion of the cell cycle. The transcription regulator cyclins, which include cyclin C, H, K, L1, T1, and T2, work together with CDK7, -8, and -9 and tend to play roles in transcriptional regulation (6). The proposed functions of cyclin G 1 and G 2 are seemingly distinct from either cell cycle or transcriptional regulation (7). Other cyclins have also been identified, but their roles in cell cycle control and RNA transcription, if any, are unclear and remain to be studied.Transcription regulator cyclin/CDK pairs are associated with the initiation, elongation, and processing of RNA transcripts. During this process cyclins interact with the large subunit of RNA polymerase II, phosphorylating the C-terminal domain (CTD) via their partner CDKs. It is widely accepted that transcription and RNA processing are closely related. Capping enzymes, polyadenylation factors, and splicing factors assemble at the CTD of RNA polymerase II. Hyperphosphorylated RNA polymerase II (RNAPIIo) stimulates RNA splicing, and the CTD has been observed to target some splicing factors to R...

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Section: Discussionsupporting

confidence: 76%

Cyclin L2, a Novel RNA Polymerase II-associated Cyclin, Is Involved in Pre-mRNA Splicing and Induces Apoptosis of Human Hepatocellular Carcinoma Cells

Yang¹,

Li²,

Wang

et al. 2004

Journal of Biological Chemistry

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“…Moreover, purified pol II, or the CTD itself, can stimulate splicing as well as the 3Ј-end processing of transcripts in vitro (17)(18)(19). Consistent with these results, factors involved in capping, splicing, and 3Ј-end formation have been found to interact with the CTD (1,3,20).…”

supporting

confidence: 62%

Transcriptional Activators Control Splicing and 3′-End Cleavage Levels

Rosonina

Bakowski

McCracken

et al. 2003

Journal of Biological Chemistry

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We have investigated whether transcriptional activators influence the efficiency of constitutive splicing and 3 -end formation, in addition to transcription levels. Remarkably, strong activators result in higher levels of splicing and 3 -cleavage than weak activators and can control the efficiency of these steps in pre-mRNA processing separately. The pre-mRNA processing stimulatory property of activators is dependent on their binding to promoters, but is not an indirect consequence of the levels of transcripts produced. Moreover, stimulation of splicing and cleavage by a strong activator operates by a mechanism that requires the carboxyl-terminal domain of RNA polymerase II. The splicing stimulatory property of activators was observed for unrelated transcripts and for separate introns within a transcript, indicating a possible general role for strong activators in facilitating pre-mRNA processing levels. The results suggest that the efficiency of constitutive splicing and 3 -end cleavage is closely coordinated with transcription levels by promoter-bound activators.The generation of mature mRNA involves the addition of an m 7 G cap at the 5Ј-end, splicing, and cleavage and polyadenylation at the 3Ј-end of precursor (pre-)mRNAs. Although these steps can occur in isolation of each other, the majority of pre-mRNA processing occurs as RNA polymerase II (pol II) 1 is transcribing. This is evident from numerous microscopy studies, in which the removal of most introns is observed to coincide with nascent transcript synthesis, as well as from more recent studies that demonstrate that transcription and pre-mRNA processing steps are physically coupled and can influence one another (1-3).The largest subunit of pol II contains a carboxyl-terminal domain (CTD), which in mammals consists of 52 repeats of the heptapeptide consensus sequence YSPTSPS (4, 5). Pol II at the stage of transcription initiation is associated with a large holoenzyme complex, which is recruited to promoters by sequence-specific transcriptional activators (6 -10). In some cases, stimulation of transcription by activators requires the CTD (11-13). Recent work has demonstrated that the CTD is also important for pre-mRNA processing. Truncation of the CTD in vivo reduces the efficiency of capping, splicing, and 3Ј-end formation (14 -16). Moreover, purified pol II, or the CTD itself, can stimulate splicing as well as the 3Ј-end processing of transcripts in vitro (17)(18)(19). Consistent with these results, factors involved in capping, splicing, and 3Ј-end formation have been found to interact with the CTD (1, 3, 20).It is not known at which stage of transcription different pre-mRNA processing components are recruited to transcription complexes, nor how CTD-associated components influence pre-mRNA processing. The 3Ј-end cleavage polyadenylation stimulatory factor (CPSF) interacts with the general transcription factor TFIID during transcription initiation (21), as well as with the CTD (15), indicating that it is recruited to transcription initiation complexes pr...

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“…In mammalian, yeast, and plant systems the CTD targets splicing factors to the site of transcription, thereby dramatically increasing splicing efficiency (36,37). This colocalization of mRNA synthesizing and splicing machinery should increase in importance as the density of introns grows within a given genome.…”

Section: Discussionmentioning

confidence: 99%

“…The hypophosphorylated CTD binds the mediator that transduces control signals to the pol II͞promoter complex (6). The CTD also recruits SR (serine-arginine) proteins and other splicing factors to the elongating message (37,49), thereby mediating alternative splicing of exon junctions to produce different tissue-specific or developmentally specific products from the same gene. Approximately 40% of genes in the human genome appear to be subject to such alternative splicing, resulting in a more than 3-fold increase in complexity of gene products over gene content (50).…”

Section: Discussionmentioning

confidence: 99%

Evolution of the RNA polymerase II C-terminal domain

Stiller

Hall

2002

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

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In recent years a great deal of biochemical and genetic research has focused on the C-terminal domain (CTD) of the largest subunit (RPB1) of DNA-dependent RNA polymerase II. This strongly conserved domain of tandemly repeated heptapeptides has been linked functionally to important steps in the initiation and processing of mRNA transcripts in both animals and fungi. Although they are absolutely required for viability in these organisms, C-terminal tandem repeats do not occur in RPB1 sequences from diverse eukaryotic taxa. Here we present phylogenetic analyses of RPB1 sequences showing that canonical CTD heptads are strongly conserved in only a subset of eukaryotic groups, all apparently descended from a single common ancestor. Moreover, eukaryotic groups in which the most complex patterns of ontogenetic development occur are descended from this CTD-containing ancestor. Consistent with the results of genetic and biochemical investigations of CTD function, these analyses suggest that the enhanced control over RNA polymerase II transcription conveyed by acquired CTD͞protein interactions was an important step in the evolution of intricate patterns of gene expression that are a hallmark of large, developmentally complex eukaryotic organisms. development ͉ RPB1 ͉ transcription E ach of the core subunits present in all cellular DNAdependent RNA polymerase (pol) enzymes shares a common evolutionary origin (1, 2). The largest of these subunits contains eight highly conserved domains, designated regions A through H (2), which are common to all prokaryotic and eukaryotic homologues (3). Unlike all other members of this protein family, however, the largest subunit of eukaryotic RNA pol II has an additional C-terminal domain (CTD), comprising a varied number of tandemly repeated heptapeptides with the consensus sequence Tyr-1-Ser-2-Pro-3-Thr-4 -Ser-5-Pro-6 -Ser-7 (4). In animals and yeast, where the mechanics of transcription are understood most clearly, the CTD has become a focal point of investigations into the interactions between RNA pol II and a variety of transcription-related proteins.Reversible phosphorylation of the CTD regulates the cycling of RNA pol II between a hypophosphorylated (IIO) form, which is competent to enter the preinitiation complex, and a hyperphosphorylated (IIA) form capable of processive transcript elongation (5). Throughout this cycle the CTD binds essential transcription-related proteins that help to regulate gene expression (6-9), promote efficient elongation (10), and effectively couple transcription to pre-mRNA processing (11-15). So central is its role in these interactions that the CTD has been called, by one reviewer, ''the tail that wags the dog'' of RNA pol II (16).Tandemly repeated CTD heptads occur in all RNA pol II largest subunits isolated to date from animals, fungi, and green plants. Given the importance of the CTD for pol II function, it is not surprising that it has been conserved so strongly during the evolution of these groups. A typical CTD also is present in certain protists;...

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A CTD function linking transcription to splicing

Cited by 146 publications

References 34 publications

Cyclin L2, a Novel RNA Polymerase II-associated Cyclin, Is Involved in Pre-mRNA Splicing and Induces Apoptosis of Human Hepatocellular Carcinoma Cells

Cyclin L2, a Novel RNA Polymerase II-associated Cyclin, Is Involved in Pre-mRNA Splicing and Induces Apoptosis of Human Hepatocellular Carcinoma Cells

Transcriptional Activators Control Splicing and 3′-End Cleavage Levels

Evolution of the RNA polymerase II C-terminal domain

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