
A long terminal repeat (LTR) is a pair of identical sequences of
DNA
Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
, several hundred
base pairs long, which occur in
eukaryotic
The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...
genomes on either end of a series of
genes
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
or
pseudogenes that form a
retrotransposon
Retrotransposons (also called Class I transposable elements) are mobile elements which move in the host genome by converting their transcribed RNA into DNA through reverse transcription. Thus, they differ from Class II transposable elements, or ...
or an
endogenous retrovirus
Endogenous retroviruses (ERVs) are endogenous viral elements in the genome that closely resemble and can be derived from retroviruses. They are abundant in the genomes of jawed vertebrates, and they comprise up to 5–8% of the human genome ( ...
or a
retroviral provirus. All retroviral genomes are flanked by LTRs, while there are some retrotransposons without LTRs. Typically, an element flanked by a pair of LTRs will encode a
reverse transcriptase
A reverse transcriptase (RT) is an enzyme used to convert RNA genome to DNA, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, by retrotransposon mobi ...
and an
integrase
Retroviral integrase (IN) is an enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme ...
, allowing the element to be copied and inserted at a different location of the genome. Copies of such an LTR-flanked element can often be found hundreds or thousands of times in a genome.
LTR retrotransposons comprise about 8% of the
human genome
The human genome is a complete set of nucleic acid sequences for humans, encoded as the DNA within each of the 23 distinct chromosomes in the cell nucleus. A small DNA molecule is found within individual Mitochondrial DNA, mitochondria. These ar ...
.
The first LTR sequences were found by A.P. Czernilofsky and
J. Shine in 1977 and 1980.
Transcription
The LTR-flanked sequences are partially
transcribed into an RNA intermediate, followed by
reverse transcription into
complementary DNA (cDNA) and ultimately dsDNA (double-stranded DNA) with full LTRs. The LTRs then mediate integration of the DNA via an LTR specific
integrase
Retroviral integrase (IN) is an enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme ...
into another region of the host
chromosome
A chromosome is a package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most import ...
.
Retroviruses such as human immunodeficiency virus (
HIV) use this basic mechanism.
Dating retroviral insertions
As 5' and 3' LTRs are identical upon insertion, the difference between paired LTRs can be used to estimate the age of ancient retroviral insertions. This method of dating is used by
paleovirologists, though it fails to take into account confounding factors such as
gene conversion and
homologous recombination
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in Cell (biology), cellular organi ...
.
HIV-1
The
HIV-1 LTR is 634 bp in length and, like other
retroviral LTRs, is segmented into the U3, R, and U5 regions. U3 and U5 has been further subdivided according to transcription factor sites and their impact on LTR activity and viral gene expression. The multi-step process of reverse transcription results in the placement of two identical LTRs, each consisting of a U3, R, and U5 region, at either end of the proviral DNA. The ends of the LTRs subsequently participate in integration of the provirus into the host
genome
A genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding genes, other functional regions of the genome such as ...
. Once the provirus has been integrated, the LTR on the 5′ end serves as the promoter for the entire retroviral genome, while the LTR at the 3′ end provides for nascent viral RNA
polyadenylation
Polyadenylation is the addition of a poly(A) tail to an RNA transcript, typically a messenger RNA (mRNA). The poly(A) tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In euka ...
and, in HIV-1, HIV-2, and SIV, encodes the accessory protein,
Nef.
All of the required signals for gene expression are found in the LTRs: Enhancer, promoter (can have both transcriptional enhancers or regulatory elements), transcription initiation (such as capping), transcription terminator and polyadenylation signal.
In HIV-1, the
5'UTR region has been characterized according to functional and structural differences into several sub-regions:
*TAR, or
trans-activation response element, plays a critical role in transcriptional activation via its interaction with viral proteins. It forms a highly stable stem–loop structure consisting of 26 base pairs with a bulge in its secondary structure that interfaces with the viral transcription activator protein
Tat.
*Poly A plays roles both in
dimerization and genome packaging since it is necessary for cleavage and
polyadenylation
Polyadenylation is the addition of a poly(A) tail to an RNA transcript, typically a messenger RNA (mRNA). The poly(A) tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In euka ...
. It has been reported that sequences upstream (U3 region) and downstream (U5 region) are needed in order to make the cleavage process efficient.
*PBS, or
primer binding site, is 18 nucleotides long and has a specific sequence that binds to the tRNA
Lys primer required for initiation of reverse transcription.
*Psi (Ψ), or the
Psi packaging element, is a unique motif involved in regulating the packaging of the viral genome into the
capsid
A capsid is the protein shell of a virus, enclosing its genetic material. It consists of several oligomeric (repeating) structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or m ...
. It is composed of four stem-loop (SL) structures with a major splicing donor site embedded in the second SL.
*DIS, or dimer initiation site, is a highly conserved RNA–RNA interacting sequence constituting the SL1 stem–loop in the Psi packaging element of many retroviruses. DIS is characterized by a conserved stem and palindromic loop that forms a
kissing-loop complex between HIV-1 RNA genomes to dimerize them for
encapsidation.
The transcript begins, at the beginning of R, is capped, and proceeds through U5 and the rest of the provirus, usually terminating by the addition of a poly A tract just after the R sequence in the 3' LTR.
The finding that both HIV LTRs can function as transcriptional promoters is not surprising since both elements are apparently identical in nucleotide sequence. Instead, the 3' LTR acts in transcription termination and polyadenylation. However, it has been suggested that the transcriptional activity of the 5' LTR is far greater than that of the 3' LTR, a situation that is very similar to that of other retroviruses.
During transcription of the human immunodeficiency virus type 1 provirus, polyadenylation signals present in the 5' long terminal repeat (LTR) are disregarded while the identical polyadenylation signals present in the 3'LTR are utilized efficiently. It has been suggested that transcribed sequences present within the HIV-1 LTR U3 region act in cis to enhance polyadenylation within the 3' LTR.
See also
*
Direct repeat
*
RetrOryza
*
LTR retrotransposon
References
External links
*
*
{{Repeated sequence
Molecular genetics