The cellular transcription factor E2F, previously identified as a component of early adenovirus transcription, has now been shown to be important in cell proliferation control. E2F appears to be a functional target for the action of the tumor suppressor protein Rb that is encoded by the retinoblastoma susceptibility gene. The disruption of this E2F-Rb interaction, as well as a complex involving E2F in association with the cell cycle-regulated cyclin A-cdk2 kinase complex, may be a common mechanism of action for the oncoproteins encoded by the DNA tumor viruses.

https://science.sciencemag.org/content/sci/258/5081/424.full.pdf

E2F: a link between the Rb tumor suppressor protein and viral oncoproteins

INTRODUCTION 339 STRUCTURAL FEATURES OF TERMINATION SITES . ......... 340 Prokaryotes ...... ..... .... ...... 341 Eukaryotes 346 FACTORS THAT REGULATE TERMINATION EFFI CIENCY AND LOCATION.... 350 Prokaryotes . . . . . . . . . . . . .. ... . . .. . . . . ... . . ... .. . . . . .. . . . . . . .. . . .. . . .. . ... . . . . . . . ......... 350 Eukaryotes 356 MECHANISTIC AND STRUCTURAL CONSIDERATIONS...... . . . ........ 359 The Dynamics of Terminati on 359 Mechanisms: Similarities and Diff erences ........ . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 361 SUMMARY, CONCLUSIONS, AND QUE STIONS FOR THE FUTURE 363

Transcription Termination and the Regulation of Gene Expression

Max L. Birnstiel, Meinrad Busslinger, and Katharina Strub Institut fL~r Molekularbiologie II der Universitt Legon et al., 1979). While transcription termina- tion is dispensable, there is some evidence that RNA processing is essential. For eXample, mutations in the polyadenylation signal in the ~2- and/~-globin genes are responsible for thalassemias in man (Higgs et al., 1983; Orkin et al., 1985). The downstream mRNA segment that is cleaved from the eukaryotic mRNA precursor in the 3' processing reac- tion is uncapped, extremely unstable in vivo, and is usu- ally available for analysis only in pulse-labeled nuclear RNA or as nascent RNA chains during run-on experi- ments. A recent estimate suggests a half life of consider- ably less than 10 minutes for the unused RNA sequences of the mouse/3-globin gene (Citron et al., 1984). Because of the great metabolic instability of the downstream tran- scripts, 3' cleavage of pre-mRNA in eukaryotes is, in many ways, the phenotypic equivalent of transcription termi- nation. The transcription termination and/or processing events responsible for generating the 3' terminus are not impor- tant merely for producing a defined end to the molecule. In several cases, alternative 3' ends can be generated, and the actual 3' end achieved in a particular molecule may in turn control processing events in preceding regions of the molecule; for instance, the pattern of splic- ing may be changed, leading to the synthesis of alterna- tive proteins. Examples are presented by complex gene units such as the heavy immunoglobulin gene (Mather et al., 1984), the adeno late transcription unit (for review, see Darnell, 1982; Nevins, 1983) and the calcitonin gene (for review, see Rosenfeld et al., 1984). Recently, it has been discovered that cell cycle regulation of histone gene ex- pression depends largely on sequences near the 3' termi- nus (L~scher et al., 1985). Thus, the events at the 3' end of mRNA provide a focal point for the study of gene regulation. Transcription Termination in Eukaryotes Is Heterogeneous and Depends on Specific DNA Sequences Downstream of the 3' Processing Site(s) In all genes of eukaryotes studied so far, with the possible exception of yeast, RNA polymerase II transcribes across the polyadenylation site(s) and terminates, sometimes very far, downstream of the DNA sequences coding for the 3' mRNA termini. This was first recognized through analy- sis of pulse-labeled RNAs of the adeno major late tran- scription unit (Nevins and Darnell, 1978; reviewed by Dar- nell, 1982; Nevins, 1983) and has, more recently, been fully supported by in vitro nuclear run-on studies on a vari- ety of chromosomal genes (Hofer et al., 1981; Sheffery et al., 1984; Weintraub et al., 1981; Mather et al., 1984; Frayne et al., 1984; Amara et al., 1984). In these latter ex- periments, transcripts of the spacer downstream of the polyadenylation site(s) were shown to be present in near equimolar amounts compared to those of the mRNA cod- ing sequences. So far, the sequences in which transcription actually ceases are ill-defined. The observation that there is a gradual reduction in hybridization of transcripts to DNA re- striction fragments distal to the genes (Hofer and Darnell, 1981; Citron et al., 1984; HagenbLichle et al., 1984) and the results of $1 mapping experiments (Hagenb~chle et al., 1984) have suggested that transcription termination oc- curs at multiple sites in a stretch of DNA extending over hundreds, or even thousands, of nucleotides. The most rapid falloff in density of transcribing polymerases was found in the chicken ovalbumin gene, where ,~90% of transcription terminates in a discrete region 900 bp down- stream of the last exon (LeMeur et al., 1984). This region extends over 170 bp and includes AT-rich sequences that resemble some terminal mRNA sequences of yeast (see below). At face value, the combined data mean that tran- scription termination in eukaryotes depends on weak, serially-repeated termination sequences. The sequences directing transcription termination are presently being investigated by sequence manipulation experiments. The first such study, carried out on a H2A histone gene, involved the classic strategy of identifying

https://www.cell.com/cell/pdf/S0092-8674(85)80007-6.pdf

Transcription Termination and 3' Processing: The End Is in Site! Review

Many genes have been described and characterized which result in alternative polyadenylation site use at the 3'-end of their mRNAs based on the cellular environment. In this survey and summary article 95 genes are discussed in which alternative polyadenylation is a consequence of tandem arrays of poly(A) signals within a single 3'-untranslated region. An additional 31 genes are described in which polyadenylation at a promoter-proximal site competes with a splicing reaction to influence expression of multiple mRNAs. Some have a composite internal/terminal exon which can be differentially processed. Others contain alternative 3'-terminal exons, the first of which can be skipped in some cells. In some cases the mRNAs formed from these three classes of genes are differentially processed from the primary transcript during the cell cycle or in a tissue-specific or developmentally specific pattern. Immunoglobulin heavy chain genes have composite exons; regulated production of two different Ig mRNAs has been shown to involve B cell stage-specific changes in trans -acting factors involved in formation of the active polyadenylation complex. Changes in the activity of some of these same factors occur during viral infection and take-over of the cellular machinery, suggesting the potential applicability of at least some aspects of the Ig model. The differential expression of a number of genes that undergo alternative poly(A) site choice or polyadenylation/splicing competition could be regulated at the level of amounts and activities of either generic or tissue-specific polyadenylation factors and/or splicing factors.

/pdf/alternative-poly-a-site-selection-in-complex-transcription-1jnaziyce6.pdf

Alternative poly(A) site selection in complex transcription units: means to an end?

Polyadenylation of pre-mRNAs requires the conserved hexanucleotide AAUAAA, as well as sequences located downstream from the poly(A) addition site. The role of these sequences in the production of functional mRNAs was studied by analyzing a series of mutants containing deletions or substitutions in the SV40 early region poly(A) site. As expected, both a previously defined GU-rich downstream element and an AAUAAA sequence were required for efficient usage of the wild-type poly(A) addition site. However, when either of these elements was deleted, greatly increased levels of SV40-specific RNA were detected in the nuclei of transfected cells. Evidence is presented that this accumulation of RNA resulted from a failure of transcription termination, leading to multiple rounds of transcription of the circular templates. We conclude that the sequences required for efficient cleavage/polyadenylation of the SV40 early pre-mRNA also constitute an important element of an RNA polymerase II termination signal. A model proposing a mechanism by which the act of pre-mRNA 3' end formation is signaled to the elongating RNA polymerase, resulting in termination, is presented.

/pdf/a-functional-mrna-polyadenylation-signal-is-required-for-ie8np2ip9o.pdf

A functional mRNA polyadenylation signal is required for transcription termination by RNA polymerase II.

We observed equimolar transcription throughout the 35-kilobase mouse dihydrofolate reductase structural gene. Transcription termination occurred within a discrete region (900 base pairs) located 1 kilobase beyond the last of seven functional polyadenylation sites and near a repetitive DNA sequence element. The results imply that a distinct genetic signal may be associated with the process of transcription termination.

Transcription of the mouse dihydrofolate reductase gene proceeds unabated through seven polyadenylation sites and terminates near a region of repeated DNA.

Infection of human cells by adenovirus results in multiple alterations of host gene expression. To examine the effects of viral infection on the expression of a single gene, a line of human cells was developed which is resistant to growth in methotrexate and which contains amplified RNA and protein specific for dihydrofolate reductase (DHFR). Cytogenetic evidence indicated the presence of amplified DNA. Adenovirus infection of these cells caused an induction and subsequent decline in the synthesis of DHFR protein. The maximum DHFR induction occurred 16 to 19 h after infection and reached a level 2.5-fold greater than that observed in uninfected cells. Induction of DHFR protein synthesis was accompanied by concomitant increases in the level of steady-state DHFR-specific cytoplasmic RNA. The relative rate of DHFR mRNA production (i.e., the appearance of DHFR-specific mRNA sequences in the cytoplasm) also increased 2.5-fold during induction. Later in infection, the relative rate of DHFR protein synthesis declined, reaching a level below that observed in uninfected cells. This decline was accompanied by a similar decline in the steady-state levels of DHFR RNA and in the relative rate of synthesis of DHFR mRNA. These data suggest that adenovirus infection controls DHFR gene expression by increasing and subsequently decreasing the relative rate at which DHFR-specific mRNA sequences appear in the cytoplasm and enter the pool of mRNA available for translation.

Control of cellular gene expression during adenovirus infection: induction and shut-off of dihydrofolate reductase gene expression by adenovirus type 2.

Amplification and molecular cloning of murine adenosine deaminase gene sequences.

Localization and sequence analysis of poly(A) sites generating multiple dihydrofolate reductase mRNAs.

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Transcription of the mouse dihydrofolate reductase gene proceeds unabated through seven polyadenylation sites and terminates near a region of repeated DNA.

Control of cellular gene expression during adenovirus infection: induction and shut-off of dihydrofolate reductase gene expression by adenovirus type 2.

Amplification and molecular cloning of murine adenosine deaminase gene sequences.

Localization and sequence analysis of poly(A) sites generating multiple dihydrofolate reductase mRNAs.