Summary: Reverse transcriptase (RNA-dependent DNA polymerase)
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Reverse transcriptase Edit Wikipedia article
(RNA-dependent DNA polymerase)
|RNA-directed DNA polymerase|
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. It is mainly associated with retroviruses. However, non-retroviruses also use RT (for example, the hepatitis B virus, a member of the Hepadnaviridae, which are dsDNA-RT viruses, while retroviruses are ssRNA viruses). RT inhibitors are widely used as antiretroviral drugs. RT activities are also associated with the replication of chromosome ends (telomerase) and some mobile genetic elements (retrotransposons).
Retroviral RT has three sequential biochemical activities:
- (a) RNA-dependent DNA polymerase activity,
- (b) ribonuclease H, and
- (c) DNA-dependent DNA polymerase activity.
These activities are used by the retrovirus to convert single-stranded genomic RNA into double-stranded cDNA which can integrate into the host genome, potentially generating a long-term infection that can be very difficult to eradicate. The same sequence of reactions is widely used in the laboratory to convert RNA to DNA for use in molecular cloning, RNA sequencing, polymerase chain reaction (PCR), or genome analysis.
Well studied reverse transcriptases include:
- HIV-1 reverse transcriptase from human immunodeficiency virus type 1 ( ) has two subunits, which have respective molecular weights of 66 and 51 kDa.
- M-MLV reverse transcriptase from the Moloney murine leukemia virus is a single 75 kDa monomer.
- AMV reverse transcriptase from the avian myeloblastosis virus also has two subunits, a 63 kDa subunit and a 95 kDa subunit.
- Telomerase reverse transcriptase that maintains the telomeres of eukaryotic chromosomes.
Reverse transcriptases were discovered by Howard Temin at the University of Wisconsin–Madison in RSV virions and independently isolated by David Baltimore in 1970 at MIT from two RNA tumour viruses: R-MLV and again RSV. For their achievements, both shared the 1975 Nobel Prize in Physiology or Medicine (with Renato Dulbecco).
The idea of reverse transcription was very unpopular at first, as it contradicted the central dogma of molecular biology, which states that DNA is transcribed into RNA, which is then translated into proteins. However, in 1970, when the scientists Howard Temin and David Baltimore both independently discovered the enzyme responsible for reverse transcription, named reverse transcriptase, the possibility that genetic information could be passed on in this manner was finally accepted.
Function in viruses
The enzymes are encoded and used by reverse-transcribing viruses, which use the enzyme during the process of replication. Reverse-transcribing RNA viruses, such as retroviruses, use the enzyme to reverse-transcribe their RNA genomes into DNA, which is then integrated into the host genome and replicated along with it. Reverse-transcribing DNA viruses, such as the hepadnaviruses, can allow RNA to serve as a template in assembling and making DNA strands. HIV infects humans with the use of this enzyme. Without reverse transcriptase, the viral genome would not be able to incorporate into the host cell, resulting in failure to replicate.
Process of reverse transcription
Reverse transcriptase creates single-stranded DNA from an RNA template.
In virus species with reverse transcriptase lacking DNA-dependent DNA polymerase activity, creation of double-stranded DNA can possibly be done by host-encoded DNA polymerase δ, mistaking the viral DNA-RNA for a primer and synthesizing a double-stranded DNA by similar mechanism as in primer removal, where the newly synthesized DNA displaces the original RNA template.
The process of reverse transcription is extremely error-prone, and it is during this step that mutations may occur. Such mutations may cause drug resistance.
Retroviruses, also referred to as class VI ssRNA-RT viruses, are RNA reverse-transcribing viruses with a DNA intermediate. Their genomes consist of two molecules of positive-sense single-stranded RNA with a 5' cap and 3' polyadenylated tail. Examples of retroviruses include the human immunodeficiency virus (HIV) and the human T-lymphotropic virus (HTLV). Creation of double-stranded DNA occurs in the cytosol as a series of these steps:
- A specific cellular tRNA acts as a primer and hybridizes to a complementary part of the virus RNA genome called the primer binding site or PBS.
- Complementary DNA then binds to the U5 (non-coding region) and R region (a direct repeat found at both ends of the RNA molecule) of the viral RNA.
- A domain on the reverse transcriptase enzyme called RNAse H degrades the 5’ end of the RNA which removes the U5 and R region.
- The primer then "jumps" to the 3’ end of the viral genome, and the newly synthesised DNA strands hybridizes to the complementary R region on the RNA.
- The first strand of complementary DNA (cDNA) is extended, and the majority of viral RNA is degraded by RNAse H.
- Once the strand is completed, second strand synthesis is initiated from the viral RNA.
- There is then another "jump" where the PBS from the second strand hybridizes with the complementary PBS on the first strand.
- Both strands are extended further and can be incorporated into the hosts genome by the enzyme integrase.
Creation of double-stranded DNA also involves strand transfer, in which there is a translocation of short DNA product from initial RNA-dependent DNA synthesis to acceptor template regions at the other end of the genome, which are later reached and processed by the reverse transcriptase for its DNA-dependent DNA activity.
Retroviral RNA is arranged in 5’ terminus to 3’ terminus. The site where the primer is annealed to viral RNA is called the primer-binding site (PBS). The RNA 5’end to the PBS site is called U5, and the RNA 3’ end to the PBS is called the leader. The tRNA primer is unwound between 14 and 22 nucleotides and forms a base-paired duplex with the viral RNA at PBS. The fact that the PBS is located near the 5’ terminus of viral RNA is unusual because reverse transcriptase synthesize DNA from 3’ end of the primer in the 5’ to 3’ direction (with respect to the RNA template). Therefore, the primer and reverse transcriptase must be relocated to 3’ end of viral RNA. In order to accomplish this reposition, multiple steps and various enzymes including DNA polymerase, ribonuclease H(RNase H) and polynucleotide unwinding are needed.
The HIV reverse transcriptase also has ribonuclease activity that degrades the viral RNA during the synthesis of cDNA, as well as DNA-dependent DNA polymerase activity that copies the sense cDNA strand into an antisense DNA to form a double-stranded viral DNA intermediate (vDNA).
Self-replicating stretches of eukaryotic genomes known as retrotransposons utilize reverse transcriptase to move from one position in the genome to another via an RNA intermediate. They are found abundantly in the genomes of plants and animals. Telomerase is another reverse transcriptase found in many eukaryotes, including humans, which carries its own RNA template; this RNA is used as a template for DNA replication.
Initial reports of reverse transcriptase in prokaryotes came as far back as 1971 (Beljanski et al., 1971a, 1972). These have since been broadly described as part of bacterial Retrons, distinct sequences that code for reverse transcriptase, and are used in the synthesis of msDNA. In order to initiate synthesis of DNA, a primer is needed. In bacteria, the primer is synthesized during replication.
Valerian Dolja of Oregon State argues that viruses due to their diversity have played an evolutionary role in the development of cellular life, with reverse transcriptase playing a central role.
Reverse transcriptase enzymes include an RNA-dependent DNA polymerase and a DNA-dependent DNA polymerase, which work together to perform transcription. In addition to the transcription function, retroviral reverse transcriptases have a domain belonging to the RNase H family, which is vital to their replication.
There are three different replication systems during the life cycle of a retrovirus. First of all, the reverse transcriptase synthesizes viral DNA from viral RNA, and then from newly made complementary DNA strand. The second replication process occurs when host cellular DNA polymerase replicates the integrated viral DNA. Lastly, RNA polymerase II transcribes the proviral DNA into RNA, which will be packed into virions. Therefore, mutation can occur during one or all of these replication steps.
Reverse transcriptase has a high error rate when transcribing RNA into DNA since, unlike most other DNA polymerases, it has no proofreading ability. This high error rate allows mutations to accumulate at an accelerated rate relative to proofread forms of replication. The commercially available reverse transcriptases produced by Promega are quoted by their manuals as having error rates in the range of 1 in 17,000 bases for AMV and 1 in 30,000 bases for M-MLV.
Other than creating single-nucleotide polymorphisms, reverse transcriptases have also been shown to be involved in processes such as transcript fusions, exon shuffling and creating artificial antisense transcripts. It has been speculated that this template switching activity of reverse transcriptase, which can be demonstrated completely in vivo, may have been one of the causes for finding several thousand unannotated transcripts in the genomes of model organisms.
As HIV uses reverse transcriptase to copy its genetic material and generate new viruses (part of a retrovirus proliferation circle), specific drugs have been designed to disrupt the process and thereby suppress its growth. Collectively, these drugs are known as reverse-transcriptase inhibitors and include the nucleoside and nucleotide analogues zidovudine (trade name Retrovir), lamivudine (Epivir) and tenofovir (Viread), as well as non-nucleoside inhibitors, such as nevirapine (Viramune).
Reverse transcriptase is commonly used in research to apply the polymerase chain reaction technique to RNA in a technique called reverse transcription polymerase chain reaction (RT-PCR). The classical PCR technique can be applied only to DNA strands, but, with the help of reverse transcriptase, RNA can be transcribed into DNA, thus making PCR analysis of RNA molecules possible. Reverse transcriptase is used also to create cDNA libraries from mRNA. The commercial availability of reverse transcriptase greatly improved knowledge in the area of molecular biology, as, along with other enzymes, it allowed scientists to clone, sequence, and characterise RNA.
Reverse transcriptase has also been employed in insulin production. By inserting eukaryotic mRNA for insulin production along with reverse transcriptase into bacteria, the mRNA could be inserted into the prokaryote's genome. Large amounts of insulin can then be created, sidestepping the need to harvest pig pancreas and other such traditional sources. Directly inserting eukaryotic DNA into bacteria would not work because it carries introns, so would not translate successfully using the bacterial ribosomes. Processing in the eukaryotic cell during mRNA production removes these introns to provide a suitable template. Reverse transcriptase converted this edited RNA back into DNA so it could be incorporated in the genome.
- cDNA library
- DNA polymerase
- Reverse transcribing virus
- RNA polymerase
- Retrotransposon marker
- "Structural basis of HIV-1 resistance to AZT by excision.". Nat. Struct. Mol. Biol. 17 (10): 1202–9. doi:10.1038/nsmb.1908. PMC . PMID 20852643.; Tu X, Das K, Han Q, Bauman JD, Clark AD, Hou X, Frenkel YV, Gaffney BL, Jones RA, Boyer PL, Hughes SH, Sarafianos SG, Arnold E (September 2010).
- Ferris, AL; Hizi, A; Showalter, SD; Pichuantes, S; Babe, L; Craik, CS; Hughes, SH (April 1990). "Immunologic and proteolytic analysis of HIV-1 reverse transcriptase structure." (PDF). Virology. 175 (2): 456–64. doi:10.1016/0042-6822(90)90430-y. PMID 1691562.
- Konishi A, Yasukawa K, Inouye K (2012). "Improving the thermal stability of avian myeloblastosis virus reverse transcriptase α-subunit by site-directed mutagenesis". Biotechnol. Lett. 34 (7): 1209–15. doi:10.1007/s10529-012-0904-9. PMID 22426840.
- Temin H. M., Mizutani S. (June 1970). "RNA-dependent DNA polymerase in virions of Rous sarcoma virus". Nature. 226 (5252): 1211–3. doi:10.1038/2261211a0. PMID 4316301.
- Baltimore D. (June 1970). "RNA-dependent DNA polymerase in virions of RNA tumour viruses". Nature. 226 (5252): 1209–11. doi:10.1038/2261209a0. PMID 4316300.
- "Central dogma reversed". Nature. 226 (5252): 1198–9. June 1970. doi:10.1038/2261198a0. PMID 5422595.
- Bio-Medicine.org - Retrovirus Retrieved on 17 Feb, 2009
- Telesnitsky A., Goff S. P. (1993). "Strong-stop strand transfer during reverse transcription". In Skalka, M. A.; Goff, S. P. Reverse transcriptase (1st ed.). New York: Cold Spring Harbor. p. 49. ISBN 0-87969-382-7.
- Bernstein A., Weiss R., Tooze J. (1985). "RNA tumor viruses". Molecular Biology of Tumor Viruses (2nd ed.). Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory.
- Doc Kaiser's Microbiology Home Page > IV. VIRUSES > F. ANIMAL VIRUS LIFE CYCLES > 3. The Life Cycle of HIV Community College of Baltimore County. Updated: Jan 2008.
- Krieger M, Scott MP, Matsudaira PT, Lodish HF, Darnell JE, Zipursky L, Kaiser C, Berk A (2004). Molecular cell biology. New York: W.H. Freeman and CO. ISBN 0-7167-4366-3.
- Hurwitz J., Leis J. P. (January 1972). "RNA-dependent DNA polymerase activity of RNA tumor viruses. I. Directing influence of DNA in the reaction". J. Virol. 9 (1): 116–29. PMC . PMID 4333538.
- Arnold, Carrie (17 July 2014). "Could Giant Viruses Be the Origin of Life on Earth?". news.nationalgeographic.com. Retrieved 29 May 2016.
- Bbenek K., Kunkel A. T. (1993). "The fidelity of retroviral reverse transcriptases". In Skalka, M. A.; Goff, P. S. Reverse transcriptase. New York: Cold Spring Harbor Laboratory Press. p. 85. ISBN 0-87969-382-7.
- Promega kit instruction manual (1999)
- Houseley J., Tollervey D. (2010). "Apparent non-canonical trans-splicing is generated by reverse transcriptase in vitro". PLoS ONE. 5 (8): e12271. doi:10.1371/journal.pone.0012271. PMC . PMID 20805885.
- Zeng X. C., Wang S. X. (June 2002). "Evidence that BmTXK beta-BmKCT cDNA from Chinese scorpion Buthus martensii Karsch is an artifact generated in the reverse transcription process". FEBS Lett. 520 (1–3): 183–4; author reply 185. doi:10.1016/S0014-5793(02)02812-0. PMID 12044895.
- van Bakel H., Nislow C., Blencowe B. J., Hughes T. R. (2011). "Response to "The Reality of Pervasive Transcription"". PLoS Biology. 9 (7): e1001102. doi:10.1371/journal.pbio.1001102.
- RNA Transcriptase at the US National Library of Medicine Medical Subject Headings (MeSH)
- animation of reverse transcriptase action and three reverse transcriptase inhibitors
- Molecule of the month (September 2002) at the RCSB PDB
- HIV Replication 3D Medical Animation. (Nov 2008). Video by Boehringer Ingelheim.
- Goodsell DS. "Molecule of the Month: Reverse Transcriptase (Sep 2002)". Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB). Retrieved 2013-01-13.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Reverse transcriptase (RNA-dependent DNA polymerase) Provide feedback
A reverse transcriptase gene is usually indicative of a mobile element such as a retrotransposon or retrovirus. Reverse transcriptases occur in a variety of mobile elements, including retrotransposons, retroviruses, group II introns, bacterial msDNAs, hepadnaviruses, and caulimoviruses.
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This tab holds annotation information from the InterPro database.
InterPro entry IPR000477
The use of an RNA template to produce DNA, for integration into the host genome and exploitation of a host cell, is a strategy employed in the replication of retroid elements, such as the retroviruses and bacterial retrons. The enzyme catalysing polymerisation is an RNA-directed DNA-polymerase, or reverse trancriptase (RT) (EC). Reverse transcriptase occurs in a variety of mobile elements, including retrotransposons, retroviruses, group II introns [PUBMED:12758069], bacterial msDNAs, hepadnaviruses, and caulimoviruses.
Retroviral reverse transcriptase is synthesised as part of the POL polyprotein that contains; an aspartyl protease, a reverse transcriptase, RNase H and integrase. POL polyprotein undergoes specific enzymatic cleavage to yield the mature proteins. The discovery of retroelements in the prokaryotes raises intriguing questions concerning their roles in bacteria and the origin and evolution of reverse transcriptases and whether the bacterial reverse transcriptases are older than eukaryotic reverse transcriptases [PUBMED:8828137].
Several crystal structures of the reverse transcriptase (RT) domain have been determined [PUBMED:1377403].
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
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This clan represents the replicative RNA dependent RNA polymerase. from a variety of RNA viruses .
The clan contains the following 9 members:Birna_RdRp Flavi_NS5 Mitovir_RNA_pol RdRP_1 RdRP_2 RdRP_3 RdRP_4 RVT_1 RVT_2
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
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|Seed source:||Published_alignment and HMM_iterative_training|
|Previous IDs:||rvt; RVT;|
|Number in seed:||69|
|Number in full:||19646|
|Average length of the domain:||168.40 aa|
|Average identity of full alignment:||15 %|
|Average coverage of the sequence by the domain:||24.63 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 17690987 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||25|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
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Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
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There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
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Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
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There are 6 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the RVT_1 domain has been found. There are 543 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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