Primary transcript

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Pre-mRNA is the first form of RNA created through transcription in protein synthesis. The pre-mRNA lacks structures that the messenger RNA (mRNA) requires. First all introns have to be removed from the transcribed RNA through a process known as splicing. Before the RNA is ready for export, a Poly(A)tail is added to the 3' end of the RNA and a 5' cap is added to the 5' end. Pre-mRNA.svg
Pre-mRNA is the first form of RNA created through transcription in protein synthesis. The pre-mRNA lacks structures that the messenger RNA (mRNA) requires. First all introns have to be removed from the transcribed RNA through a process known as splicing. Before the RNA is ready for export, a Poly(A)tail is added to the 3' end of the RNA and a 5' cap is added to the 5' end.
Micrograph of gene transcription of ribosomal RNA illustrating the growing primary transcripts Transcription label en.jpg
Micrograph of gene transcription of ribosomal RNA illustrating the growing primary transcripts

A primary transcript is the single-stranded ribonucleic acid (RNA) product synthesized by transcription of DNA, and processed to yield various mature RNA products such as mRNAs, tRNAs, and rRNAs. The primary transcripts designated to be mRNAs are modified in preparation for translation. For example, a precursor mRNA (pre-mRNA) is a type of primary transcript that becomes a messenger RNA (mRNA) after processing.

Contents

Pre-mRNA is synthesized from a DNA template in the cell nucleus by transcription. Pre-mRNA comprises the bulk of heterogeneous nuclear RNA (hnRNA). Once pre-mRNA has been completely processed, it is termed "mature messenger RNA", or simply "messenger RNA". The term hnRNA is often used as a synonym for pre-mRNA, although, in the strict sense, hnRNA may include nuclear RNA transcripts that do not end up as cytoplasmic mRNA.

There are several steps contributing to the production of primary transcripts. All these steps involve a series of interactions to initiate and complete the transcription of DNA in the nucleus of eukaryotes. Certain factors play key roles in the activation and inhibition of transcription, where they regulate primary transcript production. Transcription produces primary transcripts that are further modified by several processes. These processes include the 5' cap, 3'-polyadenylation, and alternative splicing. In particular, alternative splicing directly contributes to the diversity of mRNA found in cells. The modifications of primary transcripts have been further studied in research seeking greater knowledge of the role and significance of these transcripts. Experimental studies based on molecular changes to primary transcripts and the processes before and after transcription have led to greater understanding of diseases involving primary transcripts.

Production

The steps contributing to the production of primary transcripts involve a series of molecular interactions that initiate transcription of DNA within a cell's nucleus. Based on the needs of a given cell, certain DNA sequences are transcribed to produce a variety of RNA products to be translated into functional proteins for cellular use. To initiate the transcription process in a cell's nucleus, DNA double helices are unwound and hydrogen bonds connecting compatible nucleic acids of DNA are broken to produce two unconnected single DNA strands. [1] One strand of the DNA template is used for transcription of the single-stranded primary transcript mRNA. This DNA strand is bound by an RNA polymerase at the promoter region of the DNA. [2]

Transcription of DNA by RNA polymerase to produce primary transcript Transcription.jpg
Transcription of DNA by RNA polymerase to produce primary transcript

In eukaryotes, three kinds of RNA—rRNA, tRNA, and mRNA—are produced based on the activity of three distinct RNA polymerases, whereas, in prokaryotes, only one RNA polymerase exists to create all kinds of RNA molecules. [3] RNA polymerase II of eukaryotes transcribes the primary transcript, a transcript destined to be processed into mRNA, from the antisense DNA template in the 5' to 3' direction, and this newly synthesized primary transcript is complementary to the antisense strand of DNA. [1] RNA polymerase II constructs the primary transcript using a set of four specific ribonucleoside monophosphate residues (adenosine monophosphate (AMP), cytidine monophosphate (CMP), guanosine monophosphate (GMP), and uridine monophosphate (UMP)) that are added continuously to the 3' hydroxyl group on the 3' end of the growing mRNA. [1]

Studies of primary transcripts produced by RNA polymerase II reveal that an average primary transcript is 7,000 nucleotides in length, with some growing as long as 20,000 nucleotides in length. [2] The inclusion of both exon and intron sequences within primary transcripts explains the size difference between larger primary transcripts and smaller, mature mRNA ready for translation into protein.[ citation needed ]

Regulation

A number of factors contribute to the activation and inhibition of transcription and therefore regulate the production of primary transcripts from a given DNA template.[ citation needed ]

Activation of RNA polymerase activity to produce primary transcripts is often controlled by sequences of DNA called enhancers. Transcription factors, proteins that bind to DNA elements to either activate or repress transcription, bind to enhancers and recruit enzymes that alter nucleosome components, causing DNA to be either more or less accessible to RNA polymerase. The unique combinations of either activating or inhibiting transcription factors that bind to enhancer DNA regions determine whether or not the gene that enhancer interacts with is activated for transcription or not. [4] Activation of transcription depends on whether or not the transcription elongation complex, itself consisting of a variety of transcription factors, can induce RNA polymerase to dissociate from the Mediator complex that connects an enhancer region to the promoter. [4]

Role of transcription factors and enhancers in gene expression regulation Role of transcription factor in gene expression regulation.svg
Role of transcription factors and enhancers in gene expression regulation

Inhibition of RNA polymerase activity can also be regulated by DNA sequences called silencers. Like enhancers, silencers may be located at locations farther up or downstream from the genes they regulate. These DNA sequences bind to factors that contribute to the destabilization of the initiation complex required to activate RNA polymerase, and therefore inhibit transcription. [5]

Histone modification by transcription factors is another key regulatory factor for transcription by RNA polymerase. In general, factors that lead to histone acetylation activate transcription while factors that lead to histone deacetylation inhibit transcription. [6] Acetylation of histones induces repulsion between negative components within nucleosomes, allowing for RNA polymerase access. Deacetylation of histones stabilizes tightly coiled nucleosomes, inhibiting RNA polymerase access. In addition to acetylation patterns of histones, methylation patterns at promoter regions of DNA can regulate RNA polymerase access to a given template. RNA polymerase is often incapable of synthesizing a primary transcript if the targeted gene's promoter region contains specific methylated cytosines— residues that hinder binding of transcription-activating factors and recruit other enzymes to stabilize a tightly bound nucleosome structure, excluding access to RNA polymerase and preventing the production of primary transcripts. [4]

R-loops

R-loops are formed during transcription. An R-loop is a three-stranded nucleic acid structure containing a DNA-RNA hybrid region and an associated non-template single-stranded DNA. Actively transcribed regions of DNA often form R-loops that are vulnerable to DNA damage. Introns reduce R-loop formation and DNA damage in highly expressed yeast genes. [7]

Transcription stress

DNA damages arise in each cell, every day, with the number of damages in each cell reaching tens to hundreds of thousands, and such DNA damages can impede primary transcription. [8] The process of gene expression itself is a source of endogenous DNA damages resulting from the susceptibility of single-stranded DNA to damage. [8] Other sources of DNA damage are conflicts of the primary transcription machinery with the DNA replication machinery, and the activity of certain enzymes such as topoisomerases and base excision repair enzymes. Even though these processes are tightly regulated and are usually accurate, occasionally they can make mistakes and leave behind DNA breaks that drive chromosomal rearrangements or cell death. [8]

RNA processing

Transcription, a highly regulated phase in gene expression, produces primary transcripts. However, transcription is only the first step which should be followed by many modifications that yield functional forms of RNAs. [9] Otherwise stated, the newly synthesized primary transcripts are modified in several ways to be converted to their mature, functional forms to produce different proteins and RNAs such as mRNA, tRNA, and rRNA.[ citation needed ]

Processing

The basic primary transcript modification process is similar for tRNA and rRNA in both eukaryotic and prokaryotic cells. On the other hand, primary transcript processing varies in mRNAs of prokaryotic and eukaryotic cells. [9] For example, some prokaryotic bacterial mRNAs serve as templates for synthesis of proteins at the same time they are being produced via transcription. Alternatively, pre-mRNA of eukaryotic cells undergo a wide range of modifications prior to their transport from the nucleus to cytoplasm where their mature forms are translated. [9] These modifications are responsible for the different types of encoded messages that lead to translation of various types of products. Furthermore, primary transcript processing provides a control for gene expression as well as a regulatory mechanism for the degradation rates of mRNAs. The processing of pre-mRNA in eukaryotic cells includes 5' capping, 3' polyadenylation, and alternative splicing.[ citation needed ]

5' capping

Shortly after transcription is initiated in eukaryotes, a pre-mRNA's 5' end is modified by the addition of a 7-methylguanosine cap, also known as a 5' cap. [9] The 5' capping modification is initiated by the addition of a GTP to the 5' terminal nucleotide of the pre-mRNA in reverse orientation followed by the addition of methyl groups to the G residue. [9] 5' capping is essential for the production of functional mRNAs since the 5' cap is responsible for aligning the mRNA with the ribosome during translation. [9]

Polyadenylation

In eukaryotes, polyadenylation further modifies pre-mRNAs during which a structure called the poly-A tail is added. [9] Signals for polyadenylation, which include several RNA sequence elements, are detected by a group of proteins which signal the addition of the poly-A tail (approximately 200 nucleotides in length). The polyadenylation reaction provides a signal for the end of transcription and this reaction ends approximately a few hundred nucleotides downstream from the poly-A tail location. [9]

Alternative splicing

Eukaryotic pre-mRNAs have their introns spliced out by spliceosomes made up of small nuclear ribonucleoproteins. [10] [11]

In complex eukaryotic cells, one primary transcript is able to prepare large amounts of mature mRNAs due to alternative splicing. Alternative splicing is regulated so that each mature mRNA may encode a multiplicity of proteins.

Alternative splicing of the primary transcript Alternativ splicing.png
Alternative splicing of the primary transcript

The effect of alternative splicing in gene expression can be seen in complex eukaryotes which have a fixed number of genes in their genome yet produce much larger numbers of different gene products. [9] Most eukaryotic pre-mRNA transcripts contain multiple introns and exons. The various possible combinations of 5' and 3' splice sites in a pre-mRNA can lead to different excision and combination of exons while the introns are eliminated from the mature mRNA. Thus, various kinds of mature mRNAs are generated. [9] Alternative splicing takes place in a large protein complex called the spliceosome. Alternative splicing is crucial for tissue-specific and developmental regulation in gene expression. [9] Alternative splicing can be affected by various factors, including mutations such as chromosomal translocation.

In prokaryotes, splicing is done by autocatalytic cleavage or by endolytic cleavage. Autocatalytic cleavages, in which no proteins are involved, are usually reserved for sections that code for rRNA, whereas endolytic cleavage corresponds to tRNA precursors.

Research

5-Fluorouracil (FUra) exposure in methotrexate-resistant KB cells led to a two-fold reduction in total dihydrofolate reductase (DHFR) mRNA levels, while the level of DHFR pre-mRNA with certain introns remained unaffected. The half-life of DHFR mRNA or pre-mRNA did not change significantly, but the transition rate of DHFR RNA from the nucleus to the cytoplasm decreased, suggesting that FUra may influence mRNA processing and/or nuclear DHFR mRNA stability. [12]

In Drosophila and Aedes , hnRNA (pre-mRNA) size was larger in Aedes due to its larger genome, despite both species producing mature mRNA of similar size and sequence complexity. This indicates that hnRNA size increases with genome size. [13]

In HeLa cells, spliceosome groups on pre-mRNA were found to form within nuclear speckles, with this formation being temperature-dependent and influenced by specific RNA sequences. Pre-mRNA targeting and splicing factor loading in speckles were critical for spliceosome group formation, resulting in a speckled pattern. [14]

Recruiting pre-mRNA to nuclear speckles significantly increased splicing efficiency and protein levels, indicating that proximity to speckles enhances splicing efficiency. [15]

Research has also led to greater knowledge about certain diseases related to changes within primary transcripts. One study involved estrogen receptors and differential splicing. The article entitled, "Alternative splicing of the human estrogen receptor alpha primary transcript: mechanisms of exon skipping" by Paola Ferro, Alessandra Forlani, Marco Muselli and Ulrich Pfeffer from the laboratory of Molecular Oncology at National Cancer Research Institute in Genoa, Italy, explains that 1785 nucleotides of the region in the DNA that codes for the estrogen receptor alpha (ER-alpha) are spread over a region that holds more than 300,000 nucleotides in the primary transcript. Splicing of this pre-mRNA frequently leads to variants or different kinds of the mRNA lacking one or more exons or regions necessary for coding proteins. These variants have been associated with breast cancer progression. [16] In the life cycle of retroviruses, proviral DNA is incorporated in transcription of the DNA of the cell being infected. Since retroviruses need to change their pre-mRNA into DNA so that this DNA can be integrated within the DNA of the host it is affecting, the formation of that DNA template is a vital step for retrovirus replication. Cell type, the differentiation or changed state of the cell, and the physiological state of the cell, result in a significant change in the availability and activity of certain factors necessary for transcription. These variables create a wide range of viral gene expression. For example, tissue culture cells actively producing infectious virions of avian or murine leukemia viruses (ASLV or MLV) contain such high levels of viral RNA that 5–10% of the mRNA in a cell can be of viral origin. This shows that the primary transcripts produced by these retroviruses do not always follow the normal path to protein production and convert back into DNA in order to multiply and expand. [17]

See also

Related Research Articles

<span class="mw-page-title-main">Cell nucleus</span> Eukaryotic membrane-bounded organelle containing DNA

The cell nucleus is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, have no nuclei, and a few others including osteoclasts have many. The main structures making up the nucleus are the nuclear envelope, a double membrane that encloses the entire organelle and isolates its contents from the cellular cytoplasm; and the nuclear matrix, a network within the nucleus that adds mechanical support.

An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word intron is derived from the term intragenic region, i.e., a region inside a gene. The term intron refers to both the DNA sequence within a gene and the corresponding RNA sequence in RNA transcripts. The non-intron sequences that become joined by this RNA processing to form the mature RNA are called exons.

<span class="mw-page-title-main">Protein biosynthesis</span> Assembly of proteins inside biological cells

Protein biosynthesis is a core biological process, occurring inside cells, balancing the loss of cellular proteins through the production of new proteins. Proteins perform a number of critical functions as enzymes, structural proteins or hormones. Protein synthesis is a very similar process for both prokaryotes and eukaryotes but there are some distinct differences.

<span class="mw-page-title-main">RNA splicing</span> Process in molecular biology

RNA splicing is a process in molecular biology where a newly-made precursor messenger RNA (pre-mRNA) transcript is transformed into a mature messenger RNA (mRNA). It works by removing all the introns and splicing back together exons. For nuclear-encoded genes, splicing occurs in the nucleus either during or immediately after transcription. For those eukaryotic genes that contain introns, splicing is usually needed to create an mRNA molecule that can be translated into protein. For many eukaryotic introns, splicing occurs in a series of reactions which are catalyzed by the spliceosome, a complex of small nuclear ribonucleoproteins (snRNPs). There exist self-splicing introns, that is, ribozymes that can catalyze their own excision from their parent RNA molecule. The process of transcription, splicing and translation is called gene expression, the central dogma of molecular biology.

<span class="mw-page-title-main">Gene expression</span> Conversion of a genes sequence into a mature gene product or products

Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, proteins or non-coding RNA, and ultimately affect a phenotype. These products are often proteins, but in non-protein-coding genes such as transfer RNA (tRNA) and small nuclear RNA (snRNA), the product is a functional non-coding RNA. The process of gene expression is used by all known life—eukaryotes, prokaryotes, and utilized by viruses—to generate the macromolecular machinery for life.

<span class="mw-page-title-main">Transcription (biology)</span> Process of copying a segment of DNA into RNA

Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins produce messenger RNA (mRNA). Other segments of DNA are transcribed into RNA molecules called non-coding RNAs (ncRNAs).

<span class="mw-page-title-main">Alternative splicing</span> Process by which a gene can code for multiple proteins

Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene may be included within or excluded from the final RNA product of the gene. This means the exons are joined in different combinations, leading to different splice variants. In the case of protein-coding genes, the proteins translated from these splice variants may contain differences in their amino acid sequence and in their biological functions.

<span class="mw-page-title-main">Spliceosome</span> Molecular machine that removes intron RNA from the primary transcript

A spliceosome is a large ribonucleoprotein (RNP) complex found primarily within the nucleus of eukaryotic cells. The spliceosome is assembled from small nuclear RNAs (snRNA) and numerous proteins. Small nuclear RNA (snRNA) molecules bind to specific proteins to form a small nuclear ribonucleoprotein complex, which in turn combines with other snRNPs to form a large ribonucleoprotein complex called a spliceosome. The spliceosome removes introns from a transcribed pre-mRNA, a type of primary transcript. This process is generally referred to as splicing. An analogy is a film editor, who selectively cuts out irrelevant or incorrect material from the initial film and sends the cleaned-up version to the director for the final cut.

In genetics, a transcription terminator is a section of nucleic acid sequence that marks the end of a gene or operon in genomic DNA during transcription. This sequence mediates transcriptional termination by providing signals in the newly synthesized transcript RNA that trigger processes which release the transcript RNA from the transcriptional complex. These processes include the direct interaction of the mRNA secondary structure with the complex and/or the indirect activities of recruited termination factors. Release of the transcriptional complex frees RNA polymerase and related transcriptional machinery to begin transcription of new mRNAs.

In molecular biology, the five-prime cap is a specially altered nucleotide on the 5′ end of some primary transcripts such as precursor messenger RNA. This process, known as mRNA capping, is highly regulated and vital in the creation of stable and mature messenger RNA able to undergo translation during protein synthesis. Mitochondrial mRNA and chloroplastic mRNA are not capped.

<span class="mw-page-title-main">SR protein</span>

SR proteins are a conserved family of proteins involved in RNA splicing. SR proteins are named because they contain a protein domain with long repeats of serine and arginine amino acid residues, whose standard abbreviations are "S" and "R" respectively. SR proteins are ~200-600 amino acids in length and composed of two domains, the RNA recognition motif (RRM) region and the RS domain. SR proteins are more commonly found in the nucleus than the cytoplasm, but several SR proteins are known to shuttle between the nucleus and the cytoplasm.

<span class="mw-page-title-main">Mature messenger RNA</span> Eukaryotic RNA transcript

Mature messenger RNA, often abbreviated as mature mRNA is a eukaryotic RNA transcript that has been spliced and processed and is ready for translation in the course of protein synthesis. Unlike the eukaryotic RNA immediately after transcription known as precursor messenger RNA, mature mRNA consists exclusively of exons and has all introns removed.

<span class="mw-page-title-main">Post-transcriptional modification</span> RNA processing within a biological cell

Transcriptional modification or co-transcriptional modification is a set of biological processes common to most eukaryotic cells by which an RNA primary transcript is chemically altered following transcription from a gene to produce a mature, functional RNA molecule that can then leave the nucleus and perform any of a variety of different functions in the cell. There are many types of post-transcriptional modifications achieved through a diverse class of molecular mechanisms.

Small nuclear RNA (snRNA) is a class of small RNA molecules that are found within the splicing speckles and Cajal bodies of the cell nucleus in eukaryotic cells. The length of an average snRNA is approximately 150 nucleotides. They are transcribed by either RNA polymerase II or RNA polymerase III. Their primary function is in the processing of pre-messenger RNA (hnRNA) in the nucleus. They have also been shown to aid in the regulation of transcription factors or RNA polymerase II, and maintaining the telomeres.

Gene structure is the organisation of specialised sequence elements within a gene. Genes contain most of the information necessary for living cells to survive and reproduce. In most organisms, genes are made of DNA, where the particular DNA sequence determines the function of the gene. A gene is transcribed (copied) from DNA into RNA, which can either be non-coding (ncRNA) with a direct function, or an intermediate messenger (mRNA) that is then translated into protein. Each of these steps is controlled by specific sequence elements, or regions, within the gene. Every gene, therefore, requires multiple sequence elements to be functional. This includes the sequence that actually encodes the functional protein or ncRNA, as well as multiple regulatory sequence regions. These regions may be as short as a few base pairs, up to many thousands of base pairs long.

Cleavage and polyadenylation specificity factor (CPSF) is involved in the cleavage of the 3' signaling region from a newly synthesized pre-messenger RNA (pre-mRNA) molecule in the process of gene transcription. In eukaryotes, messenger RNA precursors (pre-mRNA) are transcribed in the nucleus from DNA by the enzyme, RNA polymerase II. The pre-mRNA must undergo post-transcriptional modifications, forming mature RNA (mRNA), before they can be transported into the cytoplasm for translation into proteins. The post-transcriptional modifications are: the addition of a 5' m7G cap, splicing of intronic sequences, and 3' cleavage and polyadenylation.

<span class="mw-page-title-main">Eukaryotic transcription</span> Transcription is heterocatalytic function of DNA

Eukaryotic transcription is the elaborate process that eukaryotic cells use to copy genetic information stored in DNA into units of transportable complementary RNA replica. Gene transcription occurs in both eukaryotic and prokaryotic cells. Unlike prokaryotic RNA polymerase that initiates the transcription of all different types of RNA, RNA polymerase in eukaryotes comes in three variations, each translating a different type of gene. A eukaryotic cell has a nucleus that separates the processes of transcription and translation. Eukaryotic transcription occurs within the nucleus where DNA is packaged into nucleosomes and higher order chromatin structures. The complexity of the eukaryotic genome necessitates a great variety and complexity of gene expression control.

<span class="mw-page-title-main">SF1 (gene)</span> Protein-coding gene in the species Homo sapiens

Splicing factor 1 also known as zinc finger protein 162 (ZFM162) is a protein that in humans is encoded by the SF1 gene.

RNA polymerase II holoenzyme is a form of eukaryotic RNA polymerase II that is recruited to the promoters of protein-coding genes in living cells. It consists of RNA polymerase II, a subset of general transcription factors, and regulatory proteins known as SRB proteins.

Numerous key discoveries in biology have emerged from studies of RNA, including seminal work in the fields of biochemistry, genetics, microbiology, molecular biology, molecular evolution, and structural biology. As of 2010, 30 scientists have been awarded Nobel Prizes for experimental work that includes studies of RNA. Specific discoveries of high biological significance are discussed in this article.

References

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  8. 1 2 3 Milano L, Gautam A, Caldecott KW (January 2024). "DNA damage and transcription stress". Mol Cell. 84 (1): 70–79. doi:10.1016/j.molcel.2023.11.014. PMID   38103560. Creative Commons by small.svg  This article incorporates text available under the CC BY 4.0 license.
  9. 1 2 3 4 5 6 7 8 9 10 11 Cooper GM (2000). "RNA Processing and Turnover". The Cell: A Molecular Approach (2nd ed.). Sunderland (MA): Sinauer Associates; 2000.
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  11. ↑ Wahl MC, Will CL, Lührmann R (February 2009). "The spliceosome: design principles of a dynamic RNP machine". Cell. 136 (4): 701–18. doi:10.1016/j.cell.2009.02.009. hdl: 11858/00-001M-0000-000F-9EAB-8 . PMID   19239890. S2CID   21330280.
  12. ↑ "5-Fluorouracil inhibits dihydrofolate reductase precursor mRNA processing and/or nuclear mRNA stability in methotrexate-resistant KB cells". The Journal of Biological Chemistry. 264 (35): 21413–21. December 1989. doi: 10.1016/S0021-9258(19)30096-1 . PMID   2592384.
  13. ↑ "hnRNA size and processing as related to different DNA content in two dipterans: Drosophila and Aedes". Cell. 5 (3): 281–90. July 1975. doi:10.1016/0092-8674(75)90103-8. PMID   807333. S2CID   39038640.
  14. ↑ "Prespliceosomal assembly on microinjected precursor mRNA takes place in nuclear speckles". Molecular Biology of the Cell. 12 (2): 393–406. February 2001. CiteSeerX   10.1.1.324.8865 . doi:10.1091/mbc.12.2.393. PMC   30951 . PMID   11179423.
  15. ↑ "Genome organization around nuclear speckles drives mRNA splicing efficiency". Nature. 629 (8014): 1165–1173. May 2024. doi:10.1038/s41586-024-07429-6. PMC   11164319 . PMID   38720076.
  16. ↑ Ferro P, Forlani A, Muselli M, Pfeffer U (September 2003). "Alternative splicing of the human estrogen receptor alpha primary transcript: mechanisms of exon skipping". International Journal of Molecular Medicine. 12 (3): 355–63. PMID   12883652.
  17. ↑ Coffin JM, Hughes SH, Varmus HE, eds. (1997). "Transcription". Retroviruses. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press.
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