(The FASEB Journal. 1998;12:1437-1446.)
© 1998 FASEB
Factors regulating the transcriptional elongation activity of RNA polymerase II
Ali Shilatifarda,1
a Edward A. Doisy Department of Biochemistry, St. Louis University School of Medicine, St. Louis, Missouri 63104, USA
 |
ABSTRACT
|
|---|
The synthesis of mature and functional messenger RNA by eukaryotic RNA polymerase II (Pol II) is a complex, multistage process requiring the cooperative action of many cellular proteins. This process, referred to collectively as the transcription cycle, proceeds via five stages: preinitiation, initiation, promoter clearance, elongation, and termination. During the past few years, fundamental studies of the elongation stage of transcription have demonstrated the existence of several families of Pol II elongation factors governing the activity of Pol II. It is now clear that the elongation stage of transcription is a critical stage for the regulation of gene expression. In fact, two of these elongation factors, ELL and elongin, have been implicated in human cancer. This article will review the proteins involved in the regulation of the elongation stage of transcription by Pol II, describing the recent experimental findings that have propelled vigorous research on the properties and function of the elongating RNA polymerase II.—Shilatifard, A. Factors regulating the transcriptional elongation activity of RNA polymerase II. FASEB J. 12, 1437–1446 (1998)
Key Words: negative elongation factor • mRNA synthesis • ELL-associated proteins • transcriptional arrest
|
INTRODUCTION
|
|---|
MOST OF THE REGULATION of gene expression that is crucial for normal growth and development occurs at the level of DNA transcription. Although the preinitiation and initiation stages of transcription have received the most attention during the past decade, the past few years have been a watershed for biochemical studies of the RNA polymerase II (Pol II)2 elongation complex: a diverse collection of transcription elongation factors and nuclear proteins that regulate the activity of Pol II during the elongation phase of messenger RNA synthesis have been identified and biochemically characterized (1–13).
Essential to the regulation of Pol II is the chromatin structure itself, and considerable breakthroughs have elucidated its role. Chromatin proteins such as histone and HMG proteins control gene expression by packaging genes into an inactive or transcriptionally repressed form. Such transcriptionally repressed genes can be activated by the action of the histone acetyltransferases and the chromatin remodeling proteins such as mammalian BRG1, yeast SWI/SNF complex, yeast RSC complex, Drosophila NURF, and Drosophila BRM complex (for review, see refs 14–22). As shown in 
Fig. 1A,
chromatin remodeling complexes can act by `loosening' nucleosomes enough to permit entry of the DNA binding transactivators, Pol II, and the basal transcription machinery to the promoter regulatory regions. This permits the initiation of transcription.
View larger version (154K):
[in this window]
[in a new window]
|
Figure 1. Messenger RNA synthesis by RNA polymerase II. A) Chromatin remodeling. The inactive chromatin is assembled into a tightly packaged nucleosomal array so that promoter sequences and enhancer binding sites are not available for Pol II and basal initiation factor binding. Activation of transcription is believed to be initiated by the action of chromatin remodeling factors (for review, see refs 14–22), which can cause `loosening' of the nucleosome enough to allow the access of DNA binding transactivators, Pol II, and basal initiation factors. B) Transcription initiation and elongation. Once promoter regions of the active genes are exposed in the presence of Pol II, general initiation factors and mediators preinitiation complexes can be formed. Upon formation of the initiation complex in the presence of NTPs, Pol II initiates transcription, clears promoter, and enters the elongation stage of transcription. For simplicity, this figure shows the simultaneous interaction of ELL2, TFIIF, P-TEFb, elongin (SIII), FACT, ELL, and SII. Whether all these factors can act together is presently unknown.
|
|
After initiation (
Fig. 1B), Pol II enters the elongation stage. Although the beginning of the transcription elongation stage by the eukaryotic Pol II is ambiguous, we know that during this process Pol II catalyzes the DNA-dependent successive polymerization of nucleoside monophosphate into an oligoribonucleotide transcript. The requirement for Pol II elongation factors was predicted from early biochemical studies of the catalytic properties of transcription elongation by the eukaryotic Pol II (23). A variety of evidence suggested that purified Pol II lacks the ability to catalyze messenger RNA (mRNA) chain elongation in vitro at rates sufficient to account for the rates of mRNA synthesis observed in vivo. Although mRNA synthesis is estimated to proceed at rates of 1200–2000 nucleotides per minute in vivo, purified Pol II synthesizes RNA in vitro at only 100–300 nucleotides per minute under optimal conditions from naked templates (24–26). In addition to its slower overall rate in vitro, transcription elongation is disrupted by frequent pausing (27, 28). Such pausing by Pol II in vitro sometimes ends with arrest. Thus, transcription elongation factors that can either increase the overall rate of transcription or prevent premature pausing and arrest by Pol II might be expected to function in the expression of many eukaryotic genes (28).
The Pol II elongation factors fall into at least three functional classes ( Table 1).
One class includes P-TEFb (1), DRB sensitivity-inducing factor (DSIF) (Spt4, Spt5) (10, 11), and SII (29–31). P-TEFb and DSIF prevent 5, 6-dichloro-1-ß-D-ribofuranosylbenzamidazole (DRB) -induced arrest and SII prevents DNA sequence-dependent arrest. The second class, which regulates the rate of transcription elongation through nucleosomes, includes FACT (facilitates chromatin transcription) (9). The third class, which operates to increase the catalytic rate of transcription elongation by altering the Km and/or the Vmax of the polymerase, includes TFIIF (32, 33), elongin (7, 34, 35), the Holo–ELL complex (4–6), and ELL2 (36) . Recent studies have demonstrated the involvement of elongin and ELL in human cancer (4, 37).
|
FACTORS REGULATING THE POSTINITIATION PROCESSIVITY OF RNA POLYMERASE II
|
|---|
Before entering productive elongation, the processivity of Pol II is controlled by the action of both negative and positive elongation factors (N-TEFs and P-TEFs). Two distinct classes of early elongation complexes have been observed (1, 10–13, 38, 39): one class undergoes abortive elongation and gives rise to short transcripts, whereas the second class surmounts early blocks and carries out productive elongation. Negative transcription elongation factors have been proposed to be responsible for abortive elongation. This common mechanism is used to control the synthesis of full-length transcripts by Pol II through an early elongation block. Such a process has been demonstrated in diverse transcription systems. Negative elongation factors such as DSIF (10, 11) and factor 2 (13) can stimulate premature stopping and termination of the initiated polymerase, resulting in the generation of short abortive transcripts.
Initial investigations revealed that the protein kinase inhibitor DRB is a potent inhibitor of synthesis of both long transcripts from partially purified transcription systems and heterogenous nuclear RNA in cultured cells (40–42). It has been proposed that DRB works by inhibition of phosphorylation of a preinitiation complex component that makes Pol II sensitive to pausing or terminating by DSIF. The negative elongation factor DSIF was identified as a component directly involved in DRB-mediated inhibition and was subsequently purified to homogeneity from HeLa cell nuclear extract. DSIF is composed of 160 kDa (p160) and 14 kDa (p14) subunits (10). DSIF subunits have been identified as the mammalian homolog of the Saccharomyces cerevisiae Spt 4 and Spt5 proteins. Spt4 and Spt5 of S. cerevisiae are conserved proteins postulated to be involved in transcription and chromatin structure (43). These proteins were initially characterized as mutations that suppress cis- and trans-acting mutations, which affect promoter function (43), and were later shown to share a common function in vivo (44). These genetic studies in yeast have demonstrated that Spt5 is essential for growth and important for transcription. In addition to their role in transcription and chromatin structure, these proteins are required for normal recombination and chromosome segregation (45, 46). All together, this evidence suggests that Spt 4 and Spt 5 are involved in the establishment and maintenance of chromatin states necessary for distinct chromosomal function.
Another component of N-TEF, factor 2, was initially identified by its ability to suppress the appearance of transcripts that were shorter than full-length transcripts during the process of transcription in vitro (13). Factor 2, which was originally purified from Drosophila extract, is a 154 kDa protein associated with the early elongation complex. Factor 2 can result in premature termination of transcription by Pol II in a manner that requires the hydrolysis of ATP (47). It is not yet clear how factor 2 interacts with the elongation complex or how ATP hydrolysis facilitates transcript release; however, it has been reported that factor 2 can form stable complexes with dsDNA or ssDNA in the absence of ATP and that ATP can destabilize the interaction of factor 2 with dsDNA but not ssDNA (47). Although such properties suggest that factor 2 might possess helicase activity, no DNA unwinding activity has yet been associated with factor 2.
The transition from abortive elongation to productive elongation is mediated by the action of positive transcription elongation factors. One such factor is the positive transcription elongation factor P-TEFb, one of the components of P-TEF (1). P-TEFb, a multisubunit complex composed of ~124 kDa and ~43 kDa polypeptides, was originally purified to homogeneity from Drosophila extract (1). P-TEFb possesses a protein kinase activity phosphorylating the COOH-terminal domain (CTD) of Pol II (38, 39, 48). Most recently, the cDNA for the small subunit of the Drosophila P-TEFb was cloned and shown to encode for a Cdc-2-related protein kinase (38). Subsequent sequence comparison of this subunit of P-TEFb suggested that human PITALRE (CDK9) could be the homolog of this Drosophila protein. Indeed, PITALRE, which was first cloned as a CDK-like kinase with an unknown function, has been shown to be a component of human P-TEFb (38). What is more interesting, several lines of evidence have indicated that P-TEFb associates with the HIV-1 Tat and is required for Tat-mediated stimulation of transcription elongation. It is now clear that the ability of HIV-1 Tat to increase the processivity of Pol II is mediated by its ability to enhance the function of the positive elongation factor P-TEFb (38, 39).
Recently, work from both Price's and Jones' (12, 49) laboratories has shown that in addition to its original subunit composition, P-TEFb consists of cyclin T subunits that are all associated with CDK9 and possess strong Pol II CTD kinase activity. How P-TEFb protects Pol II from arrest is presently unclear; however, the kinase activity associated with this elongation factor and the CTD kinase activity of TFIIH provide the strongest evidence to date that phosphorylation of the Pol II CTD plays a significant role in the regulation of transcription elongation and mRNA processing (2, 12, 50).
|
TRANSCRIPTIONAL ARREST AND RNA POLYMERASE II ELONGATION FACTOR SII
|
|---|
After entering productive elongation, the activity of Pol II is regulated by elongation factors such as SII, TFIIF, Elongin, and the ELL family of Pol II elongation factors. Transcription elongation by Pol II is a dynamic process that does not occur at a constant rate (51). Throughout its elongation phase, Pol II can encounter constrains causing pause, arrest, and termination. Although pausing presents a temporary impediment, transcriptional arrest has more potent consequences. Transcriptional arrest within the coding region of a gene would effectively repress mRNA synthesis from the affected gene. Regulation of gene expression via the elongation stage of transcription has been described for many genes (52, 53).
For quite some time researchers have known that T-rich sites scattered throughout the eukaryotic genome participate in blocking elongating Pol II. Escape from such transcriptional impediments requires transcription factor SII, a 38 kDa protein originally purified from Ehrlich ascites tumor cells by Natori and co-workers (29). During the process of DNA-dependent transcriptional arrest, Pol II undergoes a dramatic conformational change that results in a loss of contact between the 3' end of the nascent transcript and the polymerase catalytic site (28, 31, 54). This loss of contact by Pol II is due, in part, to the change from the monotonic mode of elongation to a discontinuous one. SII allows the passage of arrested Pol II from such DNA-dependent pause sites by promoting reiterative cleavage and re-extension of the nascent transcript held in Pol II's active site. The enzymatic activity required for nascent transcript cleavage dwells within Pol II. Cleavage of the nascent transcript requires a physical interaction between the RNA and Pol II and is inhibited by low concentrations of 
-amanitin. It is likely that SII-induced transcript cleavage reactivates arrested Pol II by realigning the Pol II catalytic site with the 3' end of the nascent transcript. Recent studies of the mechanism of DNA sequence dependent arrest have also revealed that in addition to the T-rich arrest sites, pausing by Pol II depends on DNA sequences downstream of the arrest site (55).
Hawley and co-workers (56) have elegantly demonstrated that in addition to its transcriptional elongation regulatory activity, SII can regulate the transcriptional fidelity and proofreading by Pol II. They have shown that the addition of SII to a transcription reaction in vitro can strikingly alter the RNA base composition. This indicates that SII governs stable incorporation of more correct and fewer incorrect nucleotides into the growing nascent RNA chain synthesized by Pol II (56). Although the physiological function of SII in vivo still remains unclear, demonstration of its in vitro activities in prevention of DNA sequence-dependent arrest and proofreading by Pol II are clear indication that the rate and fidelity of transcription by Pol II is carefully regulated in eukaryotic cells.
|
FACTORS THAT FACILITATE TRANSCRIPTION ELONGATION THROUGH NUCLEOSOMES
|
|---|
The two meters of DNA within each eukaryotic cell are intricately wrapped around a series of tiny spools called nucleosome (57). Nucleosome are primarily responsible for the structure of eukaryotic chromosome and each consists of an octamer of the H2A, H2B, H3, and H4 histone proteins. Each nucleosome holds about 145 base pairs of DNA. Whereas the density of the structure suggests the relative unavailability of the DNA strand, studies have shown that Pol II is capable of achieving high rate of transcription elongation (about 25 nucleotides/s) from tightly packed, transcriptionally active DNA in vivo (25, 58). Precisely how Pol II is able to transcribe from chromatin templates in vivo has been the subject of intense study during the past few years. In contrast to in vivo experiments, attempts to elongate Pol II transcription in vitro using reconstituted chromatin templates have not demonstrated competent chain elongation (59). We can imagine several reasons for the inability of Pol II to elongate transcription in vitro from reconstituted chromatin templates. It is possible, for example, that DNA within the transcribing region is not accessible to Pol II and that transcription from reconstituted chromatin templates requires the activity of chromatin remodeling factors to make DNA more accessible for transcription factor binding. Indeed, several molecular complexes have recently been reported to modify nucleosomes in the presence of ATP so that the DNA within the transcribing region is more accessible to the basal transcription machinery (for review, see refs 14–22).
Felsenfeld and co-workers (60, 61) have demonstrated that when the bacteriophage SP6 RNA polymerase transcribes through the nucleosome, the histone octamer steps around the polymerase by forming an internucleosomal loop that can cause intermittent pausing during the advancement of polymerase. The same mechanism also holds true for yeast Pol III (62). However, in a purified system lacking nucleosome remodeling factors, the histone octamer provided a nearly absolute block to transcription elongation by mammalian Pol II (59). This in vivo and in vitro evidence suggests that Pol II elongation complex requires the action of cellular factors to help Pol II traverse nucleosomal templates.
Recently, Luse, Reinberg, and co-workers (9) have identified and purified a factor that allows Pol II to transcribe through chromatin remodeled templates, and have named this factor FACT (facilitates chromatin transcription). FACT is a heterodimer complex consisting of two polypeptides of 140 and 80 kDa that was purified based on its ability to overcome chromatin induced transcription stalling. This complex acts subsequent to transcription initiation to release Pol II from a nucleosome-induced block to transcription elongation. Although FACT can facilitate transcription by Pol II through nucleosomal templates, its activity does not require ATP hydrolysis and cannot be synergized by Pol II elongation factors TFIIF and SII. The biochemical mechanism used by FACT to relieve the block to elongation on chromatin template is largely unknown; however, the identification of the subunits of FACT will be instrumental in dissection of its mechanism of action.
|
THE RNA POLYMERASE II ELONGATION FACTOR ELONGIN AND VON HIPPEL-LINDAU TUMOR SUPPRESSOR GENE
|
|---|
Once Pol II has entered its productive elongation stage, a series of factors can regulate its rate and processivity. Among these factors, Elongin (SIII) can suppress transient pausing by Pol II at multiple sites along the DNA. Elongin was initially purified from rat liver nuclei by its ability to increase the catalytic rate of transcription elongation from promoter-specific transcription (7). This Pol II elongation factor is a heterotrimeric complex of A, B, and C subunits with apparent molecular masses of ~110, ~18, and ~15 kDa, respectively. Biochemical and mechanistic studies have demonstrated that Elongin A is the transcriptionally active subunit of the complex and that Elongin B and C can regulate the transcriptional activity of elongin A. In vitro experimental data have demonstrated that Elongin C can interact directly with Elongin A in the absence of Elongin B and can increase the specific activity of Elongin A. On the other hand, Elongin B cannot increase the specific activity of Elongin A nor is it capable of direct physical interaction with Elongin A in the absence of Elongin C (34, 35). Biochemical studies have demonstrated that Elongin B binds directly to Elongin C and promotes the assembly and stability of the complex.
Recently, it was reported that Elongin is a potential target for regulation by the product of the von Hippel-Lindau (VHL) tumor suppressor gene (37). The VHL gene is mutated in families with VHL disease, an infrequent genetic disorder that predisposes affected individuals to an assortment of cancers including clear-cell renal carcinoma, multiple endocrine neoplasias, and renal hemangiomas (63, 64). The VHL protein can interact directly with elongin BC complex in both in vivo and in vitro experiments (37). Consistent with the idea that the VHL–Elongin BC interaction is essential for tumor suppressor activity of the VHL protein, a vast fraction of naturally occurring VHL mutants from VHL tumors and clear-cell renal carcinomas display substantially reduced binding to the Elongin BC complex. The binding of VHL and Elongin A to Elongin BC complex is mutually exclusive and depends on a short motif that is conserved between both VHL and Elongin A (37). However, contrary to the model that VHL regulates transcription elongation in normal cells via interaction with the Elongin BC complex, it appears that Elongin BC complex is 100- to 1000-fold more abundant than Elongin A and VHL in cell extracts. Such findings suggest that the model proposed that VHL regulates the transcriptional elongation activity of the Elongin complex by competing for the Elongin BC is unlikely to account for the tumor suppressor activity of the VHL protein and that VHL protein may not regulate transcriptional elongation by Pol II in normal cells (64A).
A greater understanding of the function of the VHL complex in the development of cancer necessitates a knowledge of other cellular factors that interact with this complex. In fact, it was discovered recently that the product of the Cul 2 gene, a member of a gene family that includes S. cerevisiae CDC 53 and C. elegans Cul-1, is a component of this complex (65, 66). Although the function of the Cul-2 protein in cells is not yet clear, future studies of the mechanism of interaction of Elongin BC complex and VHL protein with Cul 2 may shed more light on this subject.
|
THE ELL FAMILY OF RNA POLYMERASE II ELONGATION FACTORS AND HUMAN LEUKEMIA
|
|---|
The human ELL gene had initially been identified as a gene on chromosome 19p13.1 that undergoes frequent translocations with the trithorax-like MLL gene on chromosome 11q23 in acute myeloid leukemia (Fig 2).
However, the biochemical function of ELL was unknown (67, 68). We purified an 80 kDa Pol II elongation factor based on its ability to increase the catalytic rate of transcription elongation (4). Sequence analysis of this polypeptide revealed that four of its tryptic peptides exactly matched the sequence of the human ELL gene product. To investigate the possibility that the human ELL gene encodes a Pol II transcription factor, the ELL cDNA was cloned and expressed. We found that the recombinant ELL increased the catalytic rate of transcription elongation of Pol II by suppressing transient pausing at multiple sites along the DNA from both promoter-dependent and promoter-independent templates (4, 6).
View larger version (30K):
[in this window]
[in a new window]
|
Figure 2. Structure of the ELL fusion protein in acute myeloid leukemia (AML). The human ELL gene on chromosome 19 can undergo translocation with MLL gene on chromosome 11 in acute myeloid leukemia. The chimeric MLL-ELL protein encodes all but NH2-terminal 45 amino acids of ELL, shown in red. TRX, trithorax-like; MT, methyltransferase.
|
|
In addition to its elongation activation domain, ELL contains a novel type of Pol II interaction domain (5). This domain of ELL can negatively regulate polymerase activity in promoter-specific transcription in vitro. Addition of ELL to transcription reactions before the assembly of the preinitiation complex leads to a significant reduction in the yield of full-length runoff transcripts, perhaps by inhibiting or disrupting the preinitiation complex (5). Remarkably, the MLL-ELL translocation found in patients with AML (Fig 2, shown in red) results in the deletion of a portion of the functional domain required for inhibition of promoter-specific initiation by ELL. ELL mutants lacking the sequence that is deleted by the translocation are fully active in elongation and can interact with Pol II. However, such mutants failed to inhibit initiation by Pol II (5).
How ELL is involved in leukemia is still a mystery; however, the partner of ELL in the chimeric protein produced by the MLL-ELL translocation is the product of the MLL gene (69–72). The MLL gene encodes a large, multidomain 3968 amino acid protein. It contains an NH2-terminal A-T hook DNA binding domain, a methyltransferase-like domain, and a COOH-terminal trithorax-like region composed of a transcriptional activation domain and several contiguous zinc fingers (69–72). The MLL gene is a recurring target for translocation in a variety of clinically distinct leukemias, and several other translocation partners of MLL have been cloned (69–79). The ELL protein is the only partner of MLL whose function is known (4–6). The breakpoints of every MLL translocation create a putative oncogene that encodes nearly the entire translocation partner fused to the NH2 terminus of the MLL protein. Although all these translocations occur within the same region of MLL, each translocation is associated with a clinically distinct form of leukemia, suggesting that MLL translocation partners such as ELL play a major role in determining the leukemic phenotype. In light of this data, it was demonstrated recently that the replacement of the normal MLL gene with an MLL-AF9 chimera led to the development of leukemia in mice, which suggests that translocation is the cause for the development of AML (80).
Since the identification of ELL as a Pol II elongation factor, several lines of evidence had suggested that ELL exists in a complex with other cellular factors. Recently, ELL was purified together with three other proteins in our laboratory (6). We have named this complex the Holo–ELL complex. This ELL-containing complex was purified to homogeneity from crude rat liver extract. The subunits of the Holo–ELL complex have molecular masses of 20, 30, and 45 kDa on sodium dodecyl sulfate/polyacrylamide gel electrophoresis. The Holo–ELL complex was also shown to possess a native molecular mass of approximately 210 kDa on size exclusion chromatography (6). Unlike the ELL polypeptide, the Holo–ELL complex is not capable of negatively regulating polymerase activity in promoter-specific transcription in vitro.
The discovery of ELL-associated proteins (EAPs) that can suppress ELL's transcriptional inhibitory activity suggests that one or more EAP interacts or at least renders nonfunctional the NH2-terminal domain of the ELL protein, a domain proven to be required for ELL's transcriptional inhibitory activity (5). We have proposed that the interaction of ELL with one of the EAPs regulates the transcriptional inhibitory activity of ELL in vivo, and deletion of this functional domain of ELL (i.e., MLL–ELL translocation) bypasses this regulation (6). This hypothesis suggests a mechanism whereby the translocation could result in the loss of regulation of promoter-specific initiation of transcription, resulting in the loss of growth regulation.
|
ELL2, A MEMBER OF AN ELL FAMILY OF RNA POLYMERASE II ELONGATION FACTORS
|
|---|
ELL2, another member of the Pol II elongation factors, was cloned based on homology to ELL (49% identical and 66% similar) (36). ELL2 can also increase the catalytic rate of transcription by Pol II by suppressing the transient pausing by the enzyme at multiple sites along the DNA. Structure–function studies have localized the ELL2 elongation activation domains to an NH2-terminal region that is highly conserved with ELL (Fig 3).
Although ELL and ELL2 are related proteins, they are not similar throughout. Alignment of the open reading frames of ELL and ELL2 revealed three regions of high homology: an NH2-terminal region, a short lysine-rich region, and a COOH-terminal region that bears striking resemblance to the ZO-1 binding domain of occludin, which is an integral membrane protein localized at tight junctions in mammalian cells. ZO-1 is a member of the family of membrane-associated guanylate kinases that includes the lethal(1)discs large-1 (dlg) tumor suppressor gene of Drosophila (81–83). Recently, ZO-1 was found to translocate to the nucleus in subconfluent cells, suggesting that ZO-1 is involved in signaling pathways controlled by cell-to-cell contact (84). Whether or not the conserved COOH-terminal region 3 of ELL is capable of interacting with ZO-1 is presently unknown. Such an interaction with ZO-1 or ZO-1-like proteins would suggest a role for ELL in signaling pathways.
View larger version (32K):
[in this window]
[in a new window]
|
Figure 3. Localization of the ELL2 elongation activation domain. Based on the summary of the ELL2 mutants and their activities, the transcriptional elongation activation domain of ELL2 is shown. Conserved regions 1, 2, and 3 (R1, R2, and R3) between ELL and ELL2 are indicated. The alignment of region 3 with the COOH-terminal ZO-1 binding domain of occludin is also shown.
|
|
|
CONCLUDING REMARKS
|
|---|
Substantial and elegant observations over the past 2 years have demonstrated that the elongation stage is a key regulatory stage in transcription by Pol II. We now know the importance of DNA binding transactivator not only in initiation of transcription per se, but also in regulating the efficiency of the elongation by Pol II. Novel studies have identified positive and negative transcription elongation factors (N-TEFs and P-TEFs) that are required for regulating the postinitiation processivity of Pol II. Pioneering initiatives have characterized factors involved in the regulation of initiation and elongation of transcription by Pol II from chromatin templates. Such studies have resulted in characterization of a new class of factors (chromatin remodeling complexes) that are essential for transcription from reconstituted templates. Identification of factors such as FACT has not only demonstrated its necessity for transcription through nucleosomes, but has also shown the requirement for other unknown factors (yet to be purified) in the regulation of transcription elongation. Future identification of such factors will be instrumental in our understanding of the biochemical mechanism underlying the regulation of transcription elongation by Pol II.
Researchers have come to recognize the connection between cancer and problems with gene expression via transcription elongation. Purification and biochemical characterization of two Pol II general elongation factors, Elongin and the Holo–ELL complex, have clarified their role in human cancer. Identification of three polypeptides associated with ELL that are capable of suppressing its transcriptional inhibitory activity has illuminated the biochemical mechanism involving ELL in the development of leukemia. Future research regarding ELL and its associated factors will be directed toward understanding the mode(s) of interaction between EAPs and ELL.
Although the biochemical mechanism of transcription elongation is not yet fully clear, we can now be confident that the elongation stage of transcription will soon be understood as a set of well-defined steps. The availability of purified and recombinant Pol II elongation factors and reconstituted systems that faithfully recapitulate the elongation stage of transcription will allow the kind of biochemical analyses that are crucial for defining rate-limiting steps in the elongation stage of transcription. Understanding how these Pol II elongation factors can be affected by promoters, template DNA, nucleosomes, and other regulatory proteins is imperative for developing accurate knowledge of the elongation stage of transcription. Finally, although a detailed architecture of the elongation complex still remains largely unknown, future models of the elongation complex must be confirmed and validated by in vivo experiments. We must consider promoters, template sequences, topology, the presence of chromatin, and other accessory factors in performing in vitro experiments.
|
ACKNOWLEDGMENTS
|
|---|
The author is grateful to Dr. William S. Sly for encouragement and support and to Dr. Gewn Ericson for critical reading of this review.
|
FOOTNOTES
|
|---|
1 Correspondence: Edward A. Doisy Department of Biochemistry, St. Louis University School of Medicine, 1402 S. Grand Blvd. St. Louis, MO 63104, USA. E-mail: shilatia{at}wpogate.slu.edu. 
2 Abbreviations: N-TEF, negative transcription elongation factor; P-TEF, positive TEF; CTD, COOH-terminal domain; VHL, von Hippel-Lindau; EAPs, ELL-associated proteins; Pol II, RNA polymerase II; mRNA, messenger RNA; FACT, facilitates chromatin transcription; DRB, 5, 6-dichloro-1-ß-D-ribofuranosylbenzamidazole; DSIF, DRB sensitivity-inducing factor.
|
REFERENCES
|
|---|
-
Marshall, N. F., and Price, D. H. (1995) Purification of P-TEFb, a transcription factor required for the transition into productive elongation. J. Biol. Chem. 270, 12335–12338[Abstract/Free Full Text]
-
Yankulov, K. Y., Pandes M., McCracken, S., Bouchard, D., and Bentley, D. L. (1996) TFIIH functions in regulating transcriptional elongation by Pol II in Xenopus oocytes. Mol. Cell Biol. 16, 3291–3299[Abstract]
-
Brown, S. A., Imbalzano, A. N., and Kingston, R. E. (1996) Activator-dependent regulation of transcriptional pausing on nucleosomal templates. Genes & Dev. 10, 1479–1490[Abstract/Free Full Text]
-
Shilatifard, A., Lane, W. S., Jackson, K. W., Conaway, R. C., and Conaway, J. W. (1996) An RNA polymerase II elongation factor encoded by the human ELL gene. Science 271, 1873–1876[Abstract]
-
Shilatifard, A., Haque, D., Conaway, R. C., and Conaway, J. W. (1997) Structure and function of an RNA polymerase II elongation factor ELL. Identification of two overlapping ELL functional domains that govern its interaction with polymerase and the ternary elongation complex. J. Biol. Chem. 272, 22355–22363[Abstract/Free Full Text]
-
Shilatifard, A. (1998) Identification and purification of the Holo–ELL complex. J. Biol. Chem. 273,11212–11217[Abstract/Free Full Text]
-
Bradsher, J. N., Jackson, K. W., Conaway, R. C., and Conaway, J. W. (1993) An RNA polymerase II transcription factor SIII. I. Identification, purification, and properties. J. Biol. Chem. 268, 25587–25593[Abstract/Free Full Text]
-
Zhou, Q., and Sharp, P. A. (1996) Tat-SF1: cofactor for stimulation of transcriptional elongation by HIV-1 Tat. Science 274, 605–610[Abstract/Free Full Text]
-
Orphanides, G., LeRoy, G., Chang, C. H., Luse, D. S., and Reinberg, D. (1998) FACT, a factor that facilitates transcript elongation through nucleosomes. Cell 92, 105–116[Medline]
-
Wada, T., Takagi, T., Yamaguchi, Y., Ferdous, A., Imai, T., Hirose, S., Sugimoto, S., Yano, K., Hartzog, G. A., Winston, F., Buratowski, S., and Handa, H. (1998) DSIF, a novel transcription elongation factor that regulates Pol II processivity, is composed of human Spt4 and Spt5 homologs. Genes & Dev. 12, 343–356[Abstract/Free Full Text]
-
Hartzog, G. A., Wada, T., Handa, H., and Winston, F. (1998) Evidence that Spt4, Spt5, and Spt6 control transcription elongation by RNA polymerase II in Saccharomyces cerevisiae. Genes & Dev. 12, 357–369[Abstract/Free Full Text]
-
Peng, J., Zhu, Y., Milton, J. T., and Price, D. H. (1998) Identification of multiple cyclin subunits of human P-TEFb. Genes & Dev. 12, 755–762[Abstract/Free Full Text]
-
Xie, Z., and Price, D. H. (1996) Purification of an RNA polymerase II transcript release factor from Drosophila. J. Biol. Chem. 271, 11043–11046[Abstract/Free Full Text]
-
Grunstein, M. (1997) Histone acetylation in chromatin structure and transcription. Nature (London) 389, 349–352[Medline]
-
Tsukiyama, T., and Wu, C. (1997) Chromatin remodeling and transcription. Curr. Opin. Genet. Dev. 7, 182–191[Medline]
-
Edmondson, D., and Roth, S. (1996) Chromatin and transcription. FASEB J. 10, 1173–1182[Abstract]
-
Winston, F., and Carlson, M. (1992) Yeast SNF/SWI transcriptional activators and the SPT/SIN chromatin connection. Trends Genet. 8, 387–391[Medline]
-
Wolffe, A. P. (1997) Transcription control: repressed repeats express themselves. Curr. Biol. 7,796–798
-
Kadonaga, J. T. (1998) Eukaryotic transcription: an interlaced network of transcription factors and chromatin-modifying machines. Cell 92, 307–313[Medline]
-
Peterson, C. L. (1996) Multiple switches to turn on chromatin? Curr. Opin. Genet. Dev. 6, 171–175[Medline]
-
Kornberg, R. D., and Lorch, Y. (1995) Interplay between chromatin structure and transcription. Curr. Opin. Cell. Biol. 7, 371–375[Medline]
-
Bayle, J. H., and Crabtree, G. R. (1997) Protein acetylation: more than chromatin modification to regulate transcription. Chem. Biol.12, 885–888
-
Izban, M. G., and Luse, D. S. (1992) Factor-stimulated RNA polymerase II transcribes at physiological elongation rates on naked DNA but very poorly on chromatin templates. J. Biol. Chem. 267, 13647–13655[Abstract/Free Full Text]
-
Tennyson, C. N., Klamut, H. J., and Worton, R. G. (1995) The human dystrophin gene requires 16 hours to be transcribed and is cotranscriptionally spliced. Nat. Genet. 9, 184–190[Medline]
-
Ucker, D. S., and Yamamoto, K. R. (1984) Early events in the stimulation of mammary tumor virus RNA synthesis by glucocorticoids. Novel assays of transcription rates. J. Biol. Chem. 259, 7416–7420[Abstract/Free Full Text]
-
Thummel, C. S., Burtis, K. C., and Hogness, D. D. (1990) Spatial and temporal patterns of E74 transcription during Drosophila development. Cell 61, 101–111[Medline]
-
Reines, D., Conaway, J. W., and Conaway, R. C. (1996) The RNA polymerase II general elongation factors. Trends Biochem. Sci. 21, 351–355[Medline]
-
Uptain, S., Kane, C. M., and Chamberlin, M. J. (1997) Basic mechanisms of transcript elongation and its regulation. Annu. Rev. Biochem. 66, 117–172[Medline]
-
Sekimizu, K., Kobayashi, N., Mizuno, D., and Natori, S. (1976) Purification of a factor from Ehrlich ascites tumor cells specifically stimulating Pol II. Biochemistry 15, 5064–5070[Medline]
-
Rudd, M. D., Izban, M., and Luse, D. S. (1994) The active site of RNA polymerase II participates in transcript cleavage within arrested ternary complexes. Proc. Natl. Acad. Sci. USA 91, 8057–8061[Abstract/Free Full Text]
-
Reines, D., and Mote, J. (1993) Elongation factor SII-dependent transcription by an RNA polymerase II through a sequence-specific DNA-binding protein. Proc. Natl. Acad. Sci. USA 90, 1917–1921[Abstract/Free Full Text]
-
Price, D. H., Sluder, A. E., and Greenleaf, A. L. (1989) Dynamic interaction between a Drosophila transcription factor and RNA polymerase II. Mol. Cell. Biol. 9, 1465–1475[Abstract/Free Full Text]
-
Gu, W., and Reines, D. (1995) Identification of a decay in transcription potential that results in elongation factor dependence of Pol II. J. Biol. Chem. 270, 11238–11244[Abstract/Free Full Text]
-
Garrett, K. P., Tan, S., Bradsher, J. N., Lane, W. S., Conaway, J. W., and Conaway, R. C. (1994) Molecular cloning of an essential subunit of an RNA polymerase II elongation factor SIII. Proc. Natl. Acad. Sci. USA 91, 5237–5241[Abstract/Free Full Text]
-
Garrett, K. P., Aso, T., Bradsher, J. N., Foundling, S. I., Lane, W. S., Conaway, R. C., and Conaway, J. W. (1995) Positive regulation of general transcription factor SIII by a tailed ubiquitin homolog. Proc. Natl. Acad. Sci. USA 92, 7172–7176[Abstract/Free Full Text]
-
Shilatifard, A., Duan, R. D., Haque, D., Florence, C., Schubach, W. H., Conaway, J. W., and Conaway, R. C. (1997) ELL2, a new member of an ELL family of an RNA polymerase II elongation factors. Proc. Natl. Acad. Sci. USA 94, 3639–3643[Abstract/Free Full Text]
-
Duan, D. R., Pause, A., Burgess, W. H., Aso, T., Chen, D. Y., Garrett, K. P., Conaway, R. C., Conaway, J. W., Linehan, W. M., and Klausner, R. D. (1995) Inhibition of transcription elongation by the VHL tumor suppressor protein. Science 269, 1402–1406[Abstract/Free Full Text]
-
Zhu, Y., Peery, T., Peng, J., Ramanathan, Y., Marshall, N., Marshall, T., Amendt, B., Mathews, M. B., and Price, D. H. (1997) Transcription elongation factor P-TEFb is required for HIV-1 tat transactivation in vitro. Genes & Dev. 11, 2622–2632[Abstract/Free Full Text]
-
Mancebo, H. S., Lee, G., Flygare, J., Tomassini, J., Luu, P., Zhu, Y., Peng, J., Blau, C., Hazuda, D., Price, D., and Flores, O. (1997) P-TEFb kinase is required for HIV Tat transcriptional activation in vivo and in vitro. Genes & Dev. 11, 2633–2644[Abstract/Free Full Text]
-
Chodosh, L. A., Fire, A., Samuels, M., and Sharp, P. A. (1989) 5,6-Dichloro-1-beta-D-ribofuranosylbenzimidazole inhibits transcription elongation by Pol II in vitro. J. Biol. Chem. 264, 2250–2257[Abstract/Free Full Text]
-
Sehgal, P. B., Derman, E., Molloy, G. R., Tamm, I., and Darnell, J. E. (1976) 5,6-Dichloro-1-beta-D-ribofuranosylbenzimidazole inhibits initiation of nuclear heterogeneous RNA chains in HeLa cells. Science 22, 431–433
-
Tamm, I., and Kikuchi, T. (1979) Early termination of heterogeneous nuclear RNA transcripts in mammalian cells: accentuation by 5,6-dichloro 1-beta-D-ribofuranosylbenzimidazole. Proc. Natl. Acad. Sci. USA 76, 5750–5754[Abstract/Free Full Text]
-
Winston, F., and Carlson, M. (1992) Yeast Snf/Swi transcriptional activators and the Spt/Sin chromatin connection. Trends Genet. 8, 387–391
-
Swanson, M. S., Malone, E. A., and Winston, F. (1991) Spt5, an essential gene important for normal transcription in Saccharomyces cerevisiae, encodes an acidic nuclear protein with a carboxy-terminal repeat. Mol. Cell. Biol. 11, 3009–3019[Abstract/Free Full Text]
-
Malagon, F., and Aguilera, A. (1996) Differential intrachromosomal hyper-recombination phenotype of spt4 and spt6 mutants in S. cerevisiae. Curr. Genet. 30, 101–106[Medline]
-
Basrai, M. A., Kingsbury, J., Koshland, D. Spencer, F., and Hieter, P. (1996) Faithful chromosome transmission requires Spt4, a putative regulator of chromatin structure in Saccharomyces cerevisiae. Mol. Cell. Biol. 16, 2838–2847[Abstract]
-
Xie, Z., and Price, D. H. (1998) Unusual nucleic acid binding properties of factor 2, an Pol II transcript release factor. J. Biol. Chem. 273, 3771–3777[Abstract/Free Full Text]
-
Marshall, N. F., Peng J., Xie, Z., and Price, D. H. (1996) Control of RNA polymerase II elongation potential by a novel carboxyl-terminal domain kinase. J. Biol. Chem. 271, 27176–27183[Abstract/Free Full Text]
-
Wei, P., Garber, M. E., Fang, S.-M., Fischer, W. H., and Jones, K. A. (1998) A novel CDK9-associated C-type cyclin interacts directly with HIV-1 Tat and mediates its high-affinity, loop-specific binding to TAR RNA Cell 92, 451–462[Medline]
-
McCracken, S., Fong, N., Yankulov, K., Ballantyne, S., Pan, G., Greenblatt, J., Patterson, S. D., Wickens, M., and Bentley, D. L. (1997) The C-terminal domain of Pol II couples mRNA processing to transcription. Nature (London) 385, 357–361[Medline]
-
Kassavetis, G. A., and Chamberlin, M. J. (1981) Pausing and termination of transcription within the early region of bacteriophage T7 DNA in vitro. J. Biol. Chem. 256, 2777–2786[Abstract/Free Full Text]
-
Spencer, C. A., and Groudine, M. (1990) Transcription elongation and eukaryotic gene regulation. Oncogene 5, 777–785[Medline]
-
Wright, S. (1993) Regulation of eukaryotic gene expression by transcriptional attenuation. Mol. Biol. Cell 4, 661–668[Medline]
-
Donahue, B. A., Yin, S., Taylor, J. S., Reines, D., and Hanawalt, P. C. (1994) Transcript cleavage by Pol II arrested by a cyclobutane pyrimidine dimer in the DNA template. Proc. Natl. Acad. Sci. USA 91, 8502–8506[Abstract/Free Full Text]
-
Reeder, T. C., and Hawley, D. K. (1996) Promoter-proximal sequences modulates Pol II elongation by a novel mechanism. Cell 87, 767–777[Medline]
-
Thomas, M. J., Platas, A. A., and Hawley, D. K. (1998) Transcriptional fidelity and proofreading by Pol II. Cell 93, 627–637[Medline]
-
Kornberg, R. D., and Lorch, Y. (1991) Irresistible force meets immovable object: transcription and the nucleosome. Cell 67, 833–836[Medline]
-
Felsenfeld, G. (1992) Chromatin as an essential part of the transcriptional mechanism. Nature (London) 355, 219–224[Medline]
-
Chang, C.-H., and Luse, D. S. (1997) The H3/H4 tetramer blocks transcript elongation by Pol II in vitro. J. Biol. Chem. 272, 23427–23434[Abstract/Free Full Text]
-
Clark, D. J., and Felsenfeld, G. (1992) A nucleosome core is transferred out of the path of a transcribing polymerase. Cell 71, 11–22[Medline]
-
Studitsky, V. M., Clark, D. J., and Felsenfeld, G. (1994) A histone octamer can step around a transcribing polymerase without leaving the template. Cell 76, 371–382[Medline]
-
Studitsky, V. M., Kassavetis, G. A., Geiduschek, E. P., and Felsenfeld, G. (1997) Mechanism of transcription through the nucleosome by eukaryotic RNA polymerase. Science 278, 1960–1963[Abstract/Free Full Text]
-
Gnarra, J. R., Duan, D. R., Weng, Y., Humphrey, J. S., Chen, D. Y., Lee, S., Pause, A., Dudley, C. F., Latif, F., Kuzmin, I., Schmidt, L., Duh, F. M., Stackhouse, T., Chen, F., Kishida, T., Wei, M. H., Lerman, M. I., Zbar, B., Klausner, R. D., and Linehan, W. M. (1996) Molecular cloning of the von Hippel-Lindau tumor suppressor gene and its role in renal carcinoma. Biochim. Biophys. Acta 1242, 201–210[Medline]
-
Sekido, Y., Bader, S., Latif, F., Gnarra, J. R., Gazdar, A. F., Linehan, W. M., Zbar, B., Lerman, M. I., and Minna, J. D. (1994) Molecular analysis of the von Hippel-Lindau disease tumor suppressor gene in human lung cancer cell lines. Oncogene 9,1599–1604[Medline]
-
Conaway, W. J., Kamura, T., and Conaway, R. C. (1998) The Elongin BC complex and the von Hippel-Lindau tumor suppressor protein. Biochim. Biophys. Acta 1377, M49–M54[Medline]
-
Pause, A., Lee, S., Worrell, R. A., Chen, D. Y. T., Burgess, W. H., Linehan, W. M., and Klausner, R. D. The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins (1997) Proc. Natl. Acad. Sci. USA 94, 2156–2161
-
Lonergan, K. M., Iliopoulos, O., Ohh, M., Kamura, T., Conaway, R. C. , Conaway, J. W., and Kaelin, W. G., Jr. (1998) Regulation of hypoxia-inducible mRNAs by the von Hippel-Lindau tumor suppressor protein requires binding to complexes containing elongins B/C and Cul2. (1998) Mol. Cell. Biol. 18, 732–741[Abstract/Free Full Text]
-
Thirman, M. J., Levitan, D. A., Kobayashi, H., Simon, M. C., and Rowley, J. D. Cloning of ELL, a gene that fuses to MLL in a t(11;19)(q23'3.1) in acute myeloid leukemia (1994) Proc. Natl. Acad. Sci. USA 91, 12110–12114[Abstract/Free Full Text]
-
Mitani, K. Kanda, Y., Ogawa, S., Tanaka, T., Inazawa, J., Yazaki, Y., and Hirai, H. (1995) Cloning of several species of MLL/MEN chimeric cDNAs in myeloid leukemia with t(11;19)(q23'3.1) translocation. Blood 85, 2017–2024[Abstract/Free Full Text]
-
Tkachuk, D. C., Kohler, S., and Cleary, M. L. (1992) Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. Cell 71, 691–700[Medline]
-
Gu, Y., Nakamura, T., Alder, H., Prasad, R., Canaani, O., Cimino, G., Croce, C. M., and Canaani, E. (1992) The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene. Cell 71, 701–708[Medline]
-
Rabbitts T. H. (1994) Chromosomal translocations in human cancer. Nature (London) 372, 143–149[Medline]
-
Yu, B. D., Hess, J. L., Horning, S. E., Brown, G. A., and Korsmeyer, S. J. (1995) Altered Hox expression and segmental identity in Mll-mutant mice. Nature (London) 378, 505–508[Medline]
-
So C. W., Caldas, C., Liu, M. M., Chen, S. J., Huang, Q. H., Gu, L. J., Sham, M. H., Wiedemann, L. M., and Chan, L. C. (1997) EEN encodes for a member of a new family of proteins containing an Src homology 3 domain and is the third gene located on chromosome 19p13 that fuses to MLL in human leukemia. Proc. Natl. Acad. Sci. USA 94, 2563–2568[Abstract/Free Full Text]
-
Prasad, R., Yano, T., Sorio, C., Nakamura, T., Rallapalli, R., Gu, Y., Leshkowitz, D., Croce, C. M., and Canaani, E. (1995) Domains with transcriptional regulatory activity within the ALL1 and AF4 proteins involved in acute leukemia. Proc. Natl. Acad. Sci. USA 92, 12160–12164[Abstract/Free Full Text]
-
Rubnitz, J. E., Morrissey, J., Savage, P. A., and Cleary, M. L. (1994) ENL, the gene fused with HRX in t(11;19) leukemias, encodes a nuclear protein with transcriptional activation potential in lymphoid and myeloid cells. Blood 84,1747–1752[Abstract/Free Full Text]
-
Joh, T., Yamamoto, K., Kagami, Y., Kakuda, H., Sato, T., Yamamoto, T., Takahashi, T., Ueda, R., Kaibuchi, K., and Seto, M. (1997) Chimeric MLL products with a Ras binding cytoplasmic protein AF6 involved in t(6;11) (q27;q23) leukemia localize in the nucleus. Oncogene 15,1681–1687[Medline]
-
Super, H. G., Strissel, P. L., Sobulo, O. M., Burian, D., Reshmi, S. C., Roe, B., Zeleznik-Le, N. J., Diaz, M. O., and Rowley, J. D. (1997) Identification of complex genomic breakpoint junctions in the t(9;11) MLL-AF9 fusion gene in acute leukemia. Genes Chromosomes Cancer 20,185–195[Medline]
-
Hjorth-Sorensen, B., Pallisgaard, N., Gronholm, M., Hokland, P., Clausen, N., and Jorgensen, P. (1997) A novel MLL-AF10 fusion mRNA variant in a patient with acute myeloid leukemia detected by a new asymmetric reverse transcription PCR method. Leukemia 11, 1588–1593[Medline]
-
Borkhardt, A., Repp, R., Haas, O. A., Leis, T., Harbott, J., Kreuder, J., Hammermann, J., Henn, T., and Lampert, F. (1997) Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemia with a t(X;11)(q13;q23). Oncogene 14, 195–202[Medline]
-
Corral, J., Lavenir, I., Impey, H., Warren, A. J., Forster, A., Larson, T. A., Bell, S., McKenzie, A. N. J., King, G., and Rabbitts, T. H. (1996) An Mll-AF9 fusion gene made by homologous recombination causes acute leukemia in chimeric mice: A method to create fusion oncogenes. Cell 85, 853–861[Medline]
-
Willott, E., Balda, M. S., Fanning, A. S., Jameson, B., van Itallie, C., and Anderson J. M. (1993) The tight junction protein ZO-1 is homologous to the Drosophila discs-large tumor suppressor protein of septate junctions. Proc. Natl. Acad. Sci. USA 90, 7834–7838[Abstract/Free Full Text]
-
Furuse, M., Itoh, M., Hirase, T., Nagafuchi, A., Yonemura, Tsukita, S., and Tsukita, S. (1994) Direct association of occludin with ZO-1 and its possible involvement in the localization of occludin at tight junctions. J. Cell Biol. 127, 1617–1626[Abstract/Free Full Text]
-
Furuse, M., Hirase, T., Itoh, M., Nagafuchi, A., Yonemura, S., and Tsukita, S. (1993) Occludin: A novel integral membrane protein localizing at tight junctions. J. Cell Biol. 123, 1777–1788[Abstract/Free Full Text]
-
Gottardi, C. J., Arpin, M., Fanning, A. S., and Louvard, D. (1996) The junction-associated protein zonula occludens-1, localizes to the nucleus before the maturation and during the remodeling of cell–cell contacts. Proc. Natl. Acad. Sci. USA 93, 10779–10784[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
M. Sharma, A. A. George, B. N. Singh, N. C. Sahoo, and K. V. S. Rao
Regulation of Transcript Elongation through Cooperative and Ordered Recruitment of Cofactors
J. Biol. Chem.,
July 20, 2007;
282(29):
20887 - 20896.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Pascual-Le Tallec, F. Simone, S. Viengchareun, G. Meduri, M. J. Thirman, and M. Lombes
The Elongation Factor ELL (Eleven-Nineteen Lysine-Rich Leukemia) Is a Selective Coregulator for Steroid Receptor Functions
Mol. Endocrinol.,
May 1, 2005;
19(5):
1158 - 1169.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Zhang, C.-H. Wu, and D. S. Gilmour
Analysis of Polymerase II Elongation Complexes by Native Gel Electrophoresis: EVIDENCE FOR A NOVEL CARBOXYL-TERMINAL DOMAIN-MEDIATED TERMINATION MECHANISM
J. Biol. Chem.,
May 28, 2004;
279(22):
23223 - 23228.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Malagon, A. H. Tong, B. K. Shafer, and J. N. Strathern
Genetic Interactions of DST1 in Saccharomyces cerevisiae Suggest a Role of TFIIS in the Initiation-Elongation Transition
Genetics,
March 1, 2004;
166(3):
1215 - 1227.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-H. Wu, Y. Yamaguchi, L. R. Benjamin, M. Horvat-Gordon, J. Washinsky, E. Enerly, J. Larsson, A. Lambertsson, H. Handa, and D. Gilmour
NELF and DSIF cause promoter proximal pausing on the hsp70 promoter in Drosophila
Genes & Dev.,
June 1, 2003;
17(11):
1402 - 1414.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. A. Nedialkov, X. Q. Gong, S. L. Hovde, Y. Yamaguchi, H. Handa, J. H. Geiger, H. Yan, and Z. F. Burton
NTP-driven Translocation by Human RNA Polymerase II
J. Biol. Chem.,
May 9, 2003;
278(20):
18303 - 18312.
[Abstract]
[Full Text]
[PDF]
|
|
|
TOP
ABSTRACT
INTRODUCTION
