Ty5 retrotransposon

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The Ty5 is a type of retrotransposon native to the Saccharomyces cerevisiae organism.

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The Saccharomyces cerevisiae retrotransposon Ty5

Ty5 is one of five [1] endogenous retrotransposons native to the model organism Saccharomyces cerevisiae, all of which target integration to gene poor regions. Endogenous retrotransposons are hypothesized to target gene poor chromosomal targets in order to reduce the chance of inactivating host genes. [2] Ty1-Ty4 integrate upstream of Pol III promoters, while Ty5 targets integration to loci bound in heterochromatin. [3] In the case of Ty5, this likely occurs by means of an interaction between the C-terminus of integrase and a target protein. [4] The tight targeting patterns seen for the Ty elements are thought to be a means to limit damage to its host, which has a very gene dense genome. [5] Ty5 was discovered in the mid 1990s in the laboratory of Daniel Voytas at Iowa State University. [6] Ty5 is used as a model system by which to understand the biology of the telomere and heterochromatin. The Ty5 retrotransposon is used as a genetic model to study the architecture and dynamics of the telomeres and heterochromatin. [7]

Yeast heterochromatin and Ty5.

Heterochromatin in S. cerevisiae is composed of a wide array of proteins and plays several roles. The first stage of heterochromatin formation requires DNA binding proteins, which interact with specific cis DNA sequences at the telomeres, rDNA and HM loci. These proteins, including Rap1p and the origin recognition complex (ORC), serve as a platform for other proteins to bind, condense the DNA, and modify neighboring histones. Some of these proteins, notably Rap1p, also play other roles, including initiation of transcription. The first known step in the formation of dedicated heterochromatin is the binding of Sir4p to Rap1p (Luo, Vega-Palas et al. 2002). Sir4p is one of four ‘Silent Information Regulator’ proteins that also include Sir1p, Sir2p and Sir3p. Of these, Sir2p, Sir3p and Sir4p form the core of heterochromatin. [8] Sir4p serves as a binding site for Sir2p, which is the next to bind. Sir2p deacetylates adjacent histones, which is thought to further condense the chromatin and prevent the binding of other transcription promoting histone modification enzymes. [9] Sir3p binding follows, further condensing the heterochromatin. Sir1p plays a role in the initiation of silencing at the HM loci. A large number of other proteins act in both a synergistic and antagonistic manner. [10]

Early work characterizing Ty5 targeted transposition focused on two fronts: identifying the component of Ty5 responsible for targeting and identifying the factor with which it interacted. Due to the central role of the Sir proteins in heterochromatin formation, they were initially considered as potential targeting signals. Because integration is mediated by the retrotransposon integrase enzyme, it was speculated to contain a component that would recognize heterochromatin. The C-terminus of the Ty retrotransposon’s integrase contains an extension not seen in the retroviruses. This region is also not conserved between Ty1 and Ty5, whereas the rest of the integrase is, suggesting that this divergence could be responsible for the different targeting of the yeast Ty elements. A mutation was identified in the integrase C-terminus that randomized Ty5 integration, suggesting that this region of integrase was in fact involved in targeted transposition. [4]

Implications for human health and disease

Ty5 is a relative of the Retroviridae family of retroviruses, which includes the human pathogen HIV. Ty5 is a tractable system in which to study the biology of retrovirus integration.

Related Research Articles

Histone Family proteins package and order the DNA into structural units called nucleosomes.

In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wrapped into 30-nanometer fibers that form tightly packed chromatin. Histones prevent DNA from becoming tangled and protect it from DNA damage. In addition, histones play important roles in gene regulation and DNA replication. Without histones, unwound DNA in chromosomes would be very long. For example, each human cell has about 1.8 meters of DNA if completely stretched out; however, when wound about histones, this length is reduced to about 90 micrometers (0.09 um) of 30 nm diameter chromatin fibers.

Retrovirus Family of viruses

A retrovirus is a type of virus that inserts a copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase enzyme to produce DNA from its RNA genome, the reverse of the usual pattern, thus retro (backwards). The new DNA is then incorporated into the host cell genome by an integrase enzyme, at which point the retroviral DNA is referred to as a provirus. The host cell then treats the viral DNA as part of its own genome, transcribing and translating the viral genes along with the cell's own genes, producing the proteins required to assemble new copies of the virus.

Transposable element Semiparasitic DNA sequence

A transposable element is a DNA sequence that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Transposition often results in duplication of the same genetic material. Barbara McClintock's discovery of them earned her a Nobel Prize in 1983.

Heterochromatin is a tightly packed form of DNA or condensed DNA, which comes in multiple varieties. These varieties lie on a continuum between the two extremes of constitutive heterochromatin and facultative heterochromatin. Both play a role in the expression of genes. Because it is tightly packed, it was thought to be inaccessible to polymerases and therefore not transcribed; however, according to Volpe et al. (2002), and many other papers since, much of this DNA is in fact transcribed, but it is continuously turned over via RNA-induced transcriptional silencing (RITS). Recent studies with electron microscopy and OsO4 staining reveal that the dense packing is not due to the chromatin.

Retrotransposon Type of genetic component

Retrotransposons are a type of genetic component that copy and paste themselves into different genomic locations (transposon) by converting RNA back into DNA through the process reverse transcription using an RNA transposition intermediate.

Constitutive heterochromatin

Constitutive heterochromatin domains are regions of DNA found throughout the chromosomes of eukaryotes. The majority of constitutive heterochromatin is found at the pericentromeric regions of chromosomes, but is also found at the telomeres and throughout the chromosomes. In humans there is significantly more constitutive heterochromatin found on chromosomes 1, 9, 16, 19 and Y. Constitutive heterochromatin is composed mainly of high copy number tandem repeats known as satellite repeats, minisatellite and microsatellite repeats, and transposon repeats. In humans these regions account for about 200Mb or 6.5% of the total human genome, but their repeat composition makes them difficult to sequence, so only small regions have been sequenced.

Endogenous retrovirus Inherited retrovirus encoded in an organisms genome

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.

Subtelomeres are segments of DNA between telomeric caps and chromatin.

An insulator is a type of cis-regulatory element known as a long-range regulatory element. Found in multicellular eukaryotes and working over distances from the promoter element of the target gene, an insulator is typically 300 bp to 2000 bp in length. Insulators contain clustered binding sites for sequence specific DNA-binding proteins and mediate intra- and inter-chromosomal interactions.

Exon shuffling is a molecular mechanism for the formation of new genes. It is a process through which two or more exons from different genes can be brought together ectopically, or the same exon can be duplicated, to create a new exon-intron structure. There are different mechanisms through which exon shuffling occurs: transposon mediated exon shuffling, crossover during sexual recombination of parental genomes and illegitimate recombination.

Long terminal repeat

A long terminal repeat (LTR) is a pair of identical sequences of DNA, several hundred base pairs long, which occur in eukaryotic genomes on either end of a series of genes or pseudogenes that form a retrotransposon or an endogenous retrovirus 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 and an integrase, 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 family of heterochromatin protein 1 (HP1) consists of highly conserved proteins, which have important functions in the cell nucleus. These functions include gene repression by heterochromatin formation, transcriptional activation, regulation of binding of cohesion complexes to centromeres, sequestration of genes to the nuclear periphery, transcriptional arrest, maintenance of heterochromatin integrity, gene repression at the single nucleosome level, gene repression by heterochromatization of euchromatin, and DNA repair. HP1 proteins are fundamental units of heterochromatin packaging that are enriched at the centromeres and telomeres of nearly all eukaryotic chromosomes with the notable exception of budding yeast, in which a yeast-specific silencing complex of SIR proteins serve a similar function. Members of the HP1 family are characterized by an N-terminal chromodomain and a C-terminal chromoshadow domain, separated by a hinge region. HP1 is also found at some euchromatic sites, where its binding can correlate with either gene repression or gene activation. HP1 was originally discovered by Tharappel C James and Sarah Elgin in 1986 as a factor in the phenomenon known as position effect variegation in Drosophila melanogaster.

HIV integration

AIDS is caused by the human immunodeficiency virus (HIV). Individuals with HIV have what is referred to as a "HIV infection". When infected semen, vaginal secretions, or blood come in contact with the mucous membranes or broken skin of an uninfected person, HIV may be transferred to the uninfected person, causing another infection. Additionally, HIV can also be passed from infected pregnant women to their uninfected baby during pregnancy and/or delivery, or via breastfeeding. As a result of HIV infection, a portion of these individuals will progress and go on to develop clinically significant AIDS.

LTR retrotransposon Class I transposable element

LTR retrotransposons are class I transposable element characterized by the presence of long terminal repeats (LTRs) directly flanking an internal coding region. As retrotransposons, they mobilize through reverse transcription of their mRNA and integration of the newly created cDNA into another location. Their mechanism of retrotransposition is shared with retroviruses, with the difference that most LTR-retrotransposons do not form infectious particles that leave the cells and therefore only replicate inside their genome of origin. Those that do (occasionally) form virus-like particles are classified under Ortervirales.

Cryptic unstable transcripts (CUTs) are a subset of non-coding RNAs (ncRNAs) that are produced from intergenic and intragenic regions. CUTs were first observed in S. cerevisiae yeast models and are found in most eukaryotes. Some basic characteristics of CUTs include a length of around 200–800 base pairs, a 5' cap, poly-adenylated tail, and rapid degradation due to the combined activity of poly-adenylating polymerases and exosome complexes. CUT transcription occurs through RNA Polymerase II and initiates from nucleosome-depleted regions, often in an antisense orientation. To date, CUTs have a relatively uncharacterized function but have been implicated in a number of putative gene regulation and silencing pathways. Thousands of loci leading to the generation of CUTs have been described in the yeast genome. Additionally, stable uncharacterized transcripts, or SUTs, have also been detected in cells and bear many similarities to CUTs but are not degraded through the same pathways.

Transcription activator-like effector nuclease

Transcription activator-like effector nucleases (TALEN) are restriction enzymes that can be engineered to cut specific sequences of DNA. They are made by fusing a TAL effector DNA-binding domain to a DNA cleavage domain. Transcription activator-like effectors (TALEs) can be engineered to bind to practically any desired DNA sequence, so when combined with a nuclease, DNA can be cut at specific locations. The restriction enzymes can be introduced into cells, for use in gene editing or for genome editing in situ, a technique known as genome editing with engineered nucleases. Alongside zinc finger nucleases and CRISPR/Cas9, TALEN is a prominent tool in the field of genome editing.

SilentInformationRegulator (SIR) proteins are involved in regulating gene expression. SIR proteins organize heterochromatin near telomeres, rDNA, and at silent loci including hidden mating type loci in yeast. The SIR family of genes encodes catalytic and non-catalytic proteins that are involved in de-acetylation of histone tails and the subsequent condensation of chromatin around a SIR protein scaffold. Some SIR family members are conserved from yeast to humans.

Daniel Voytas

Daniel Voytas, Ph.D., is Professor of Genetics, Cell Biology and Development at the University of Minnesota and Director of the Center for Precision Plant Genomics. He is also the Chief Scientific Officer of Calyxt, an agricultural biotechnology company focused on developing crops that provide consumer benefit.

Thomas Jenuwein German scientist

Thomas Jenuwein is a German scientist working in the fields of epigenetics, chromatin biology, gene regulation and genome function.

RNA-directed DNA methylation RNA-based gene silencing proces

RNA-directed DNA methylation (RdDM) is a biological process in which non-coding RNA molecules direct the addition of DNA methylation to specific DNA sequences. The RdDM pathway is unique to plants, although other mechanisms of RNA-directed chromatin modification have also been described in fungi and animals. To date, the RdDM pathway is best characterized within angiosperms, and particularly within the model plant Arabidopsis thaliana. However, conserved RdDM pathway components and associated small RNAs (sRNAs) have also been found in other groups of plants, such as gymnosperms and ferns. The RdDM pathway closely resembles other sRNA pathways, particularly the highly conserved RNAi pathway found in fungi, plants, and animals. Both the RdDM and RNAi pathways produce sRNAs and involve conserved Argonaute, Dicer and RNA-dependent RNA polymerase proteins.

References

  1. ↑ Kim JM, Vanguri S, Boeke JD, Gabriel A, Voytas DF (May 1998). "Transposable elements and genome organization: a comprehensive survey of retrotransposons revealed by the complete Saccharomyces cerevisiae genome sequence". Genome Res. 8 (5): 464–78. doi: 10.1101/gr.8.5.464 . PMID   9582191.
  2. ↑ Lesage P, Todeschini AL (2005). "Happy together: the life and times of Ty retrotransposons and their hosts". Cytogenet. Genome Res. 110 (1–4): 70–90. doi:10.1159/000084940. PMID   16093660. S2CID   40913336.
  3. ↑ Sandmeyer SB, Hansen LJ, Chalker DL (1990). "Integration specificity of retrotransposons and retroviruses". Annu. Rev. Genet. 24: 491–518. doi:10.1146/annurev.ge.24.120190.002423. PMID   1965102.
  4. 1 2 Gai X, Voytas DF (June 1998). "A single amino acid change in the yeast retrotransposon Ty5 abolishes targeting to silent chromatin". Mol. Cell. 1 (7): 1051–5. doi: 10.1016/S1097-2765(00)80105-7 . PMID   9651588.
  5. ↑ Zagulski M, Herbert CJ, Rytka J (1998). "Sequencing and functional analysis of the yeast genome". Acta Biochim. Pol. 45 (3): 627–43. doi: 10.18388/abp.1998_4201 . PMID   9918489.
  6. ↑ Zou S, Wright DA, Voytas DF (January 1995). "The Saccharomyces Ty5 retrotransposon family is associated with origins of DNA replication at the telomeres and the silent mating locus HMR". Proc. Natl. Acad. Sci. U.S.A. 92 (3): 920–4. Bibcode:1995PNAS...92..920Z. doi: 10.1073/pnas.92.3.920 . PMC   42732 . PMID   7846079.
  7. ↑ Zou S, Kim JM, Voytas DF (December 1996). "The Saccharomyces retrotransposon Ty5 influences the organization of chromosome ends". Nucleic Acids Res. 24 (23): 4825–31. doi:10.1093/nar/24.23.4825. PMC   146320 . PMID   8972872.
  8. ↑ Rine J, Herskowitz I (May 1987). "Four genes responsible for a position effect on expression from HML and HMR in Saccharomyces cerevisiae". Genetics. 116 (1): 9–22. doi:10.1093/genetics/116.1.9. PMC   1203125 . PMID   3297920.
  9. ↑ Tanner KG, Landry J, Sternglanz R, Denu JM (December 2000). "Silent information regulator 2 family of NAD- dependent histone/protein deacetylases generates a unique product, 1-O-acetyl-ADP-ribose". Proc. Natl. Acad. Sci. U.S.A. 97 (26): 14178–82. Bibcode:2000PNAS...9714178T. doi: 10.1073/pnas.250422697 . PMC   18891 . PMID   11106374.
  10. ↑ Pryde FE, Louis EJ (November 1997). "Saccharomyces cerevisiae telomeres. A review". Biochemistry Mosc. 62 (11): 1232–41. PMID   9467847.
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