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Recent Progress in Understanding the Mechanism and Consequences of Retrotransposon Movement

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A special issue of Viruses (ISSN 1999-4915).

Deadline for manuscript submissions: closed (31 January 2017) | Viewed by 82686

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Prof. David J. Garfinkel

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Guest Editor

Department of Biochemistry & Molecular Biology; University of Georgia, Athens, GA 30602, USA
Interests: retrotransposons; host interactions; restriction factors; gene expression; yeast genetics

Dr. Katarzyna J. Purzycka

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Guest Editor

Department of Structural Chemistry and Biology of Nucleic Acids, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
Interests: RNA structure; RNA folding; retrotransposons; reverse transcription; genomics

Special Issue Information

Dear Colleagues,

Retrotransposons are present in essentially all eukaryotic genomes and come in two basic flavors: those that are bracketed by long terminal repeats (LTRs) and share a common ancestor with retroviruses, and non-LTR retrotransposons that have a distinct lineage and remain transpositionally active in humans. Both types of retrotransposons replicate through an RNA intermediate, stably integrate into the host genome and have accumulated to a very high copy number in mammals and certain plant species. Autonomous elements produce transcripts capable of undergoing reverse transcription, and minimally encode proteins with reverse transcriptase, integrase/endonucleolytic, and nucleic acid chaperone activities. Retrotransposons are currently distinguished from viruses, since the process of retrotransposition is not infectious. However, this boundary may prove to be provisional as we learn more about these mobile genetic elements. The goal of this Special Issue of Viruses is to highlight progress in understanding the mechanism and consequences of retrotransposon movement. Several active research areas may be covered in reviews and research articles, including the roles of cellular modulators and defense systems, retrotransposon expression and replication, retrotransposon-induced mutations and their association with human diseases, and how these widely disseminated elements mold eukaryotic genomes.

Prof. David J. Garfinkel
Dr. Katarzyna J. Purzycka
Guest Editors

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Keywords

LTR retrotransposon
Endogenous retrovirus
Non-LTR retrotransposon
Reverse transcription
Integration
Host factors
Genome evolution
Human disease

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Published Papers (10 papers)

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Research

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1970 KiB

Open AccessArticle

Structure-Function Model for Kissing Loop Interactions That Initiate Dimerization of Ty1 RNA

by Eric R. Gamache, Jung H. Doh, Justin Ritz, Alain Laederach, Stanislav Bellaousov, David H. Mathews and M. Joan Curcio

Viruses 2017, 9(5), 93; https://doi.org/10.3390/v9050093 - 26 Apr 2017

Cited by 7 | Viewed by 5562

Abstract

The genomic RNA of the retrotransposon Ty1 is packaged as a dimer into virus-like particles. The 5′ terminus of Ty1 RNA harbors cis-acting sequences required for translation initiation, packaging and initiation of reverse transcription (TIPIRT). To identify RNA motifs involved in dimerization and packaging, a structural model of the TIPIRT domain in vitro was developed from single-nucleotide resolution RNA structural data. In general agreement with previous models, the first 326 nucleotides of Ty1 RNA form a pseudoknot with a 7-bp stem (S1), a 1-nucleotide interhelical loop and an 8-bp stem (S2) that delineate two long, structured loops. Nucleotide substitutions that disrupt either pseudoknot stem greatly reduced helper-Ty1-mediated retrotransposition of a mini-Ty1, but only mutations in S2 destabilized mini-Ty1 RNA in cis and helper-Ty1 RNA in trans. Nested in different loops of the pseudoknot are two hairpins with complementary 7-nucleotide motifs at their apices. Nucleotide substitutions in either motif also reduced retrotransposition and destabilized mini- and helper-Ty1 RNA. Compensatory mutations that restore base-pairing in the S2 stem or between the hairpins rescued retrotransposition and RNA stability in cis and trans. These data inform a model whereby a Ty1 RNA kissing complex with two intermolecular kissing-loop interactions initiates dimerization and packaging. Full article

(This article belongs to the Special Issue Recent Progress in Understanding the Mechanism and Consequences of Retrotransposon Movement)

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3021 KiB

Open AccessArticle

LTR-Retrotransposons from Bdelloid Rotifers Capture Additional ORFs Shared between Highly Diverse Retroelement Types

by Fernando Rodriguez, Aubrey W. Kenefick and Irina R. Arkhipova

Viruses 2017, 9(4), 78; https://doi.org/10.3390/v9040078 - 11 Apr 2017

Cited by 10 | Viewed by 5686

Abstract

Rotifers of the class Bdelloidea, microscopic freshwater invertebrates, possess a highlydiversified repertoire of transposon families, which, however, occupy less than 4% of genomic DNA in the sequenced representative Adineta vaga. We performed a comprehensive analysis of A. vaga retroelements, and found that bdelloid long terminal repeat (LTR)retrotransposons, in addition to conserved open reading frame (ORF) 1 and ORF2 corresponding to gag and pol genes, code for an unusually high variety of ORF3 sequences. Retrovirus-like LTR families in A. vaga belong to four major lineages, three of which are rotiferspecific and encode a dUTPase domain. However only one lineage contains a canonical envlike fusion glycoprotein acquired from paramyxoviruses (non-segmented negative-strand RNA viruses), although smaller ORFs with transmembrane domains may perform similar roles. A different ORF3 type encodes a GDSL esterase/lipase, which was previously identified as ORF1 in several clades of non-LTR retrotransposons, and implicated in membrane targeting. Yet another ORF3 type appears in unrelated LTR-retrotransposon lineages, and displays strong homology to DEDDy-type exonucleases involved in 3′-end processing of RNA and single-stranded DNA. Unexpectedly, each of the enzymatic ORF3s is also associated with different subsets of Penelope-like Athena retroelement families. The unusual association of the same ORF types with retroelements from different classes reflects their modular structure with a high degree of flexibility, and points to gene sharing between different groups of retroelements. Full article

(This article belongs to the Special Issue Recent Progress in Understanding the Mechanism and Consequences of Retrotransposon Movement)

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11752 KiB

Open AccessArticle

Structure of Ty1 Internally Initiated RNA Influences Restriction Factor Expression

by Leszek Błaszczyk, Marcin Biesiada, Agniva Saha, David J. Garfinkel and Katarzyna J. Purzycka

Viruses 2017, 9(4), 74; https://doi.org/10.3390/v9040074 - 10 Apr 2017

Cited by 9 | Viewed by 5351

Abstract

The long-terminal repeat retrotransposon Ty1 is the most abundant mobile genetic element in many Saccharomyces cerevisiae isolates. Ty1 retrotransposons contribute to the genetic diversity of host cells, but they can also act as an insertional mutagen and cause genetic instability. Interestingly, retrotransposition occurs at a low level despite a high level of Ty1 RNA, even though S. cerevisiae lacks the intrinsic defense mechanisms that other eukaryotes use to prevent transposon movement. p22 is a recently discovered Ty1 protein that inhibits retrotransposition in a dose-dependent manner. p22 is a truncated form of Gag encoded by internally initiated Ty1i RNA that contains two closely-spaced AUG codons. Mutations of either AUG codon compromise p22 translation. We found that both AUG codons were utilized and that translation efficiency depended on the Ty1i RNA structure. Structural features that stimulated p22 translation were context dependent and present only in Ty1i RNA. Destabilization of the 5′ untranslated region (5′ UTR) of Ty1i RNA decreased the p22 level, both in vitro and in vivo. Our data suggest that protein factors such as Gag could contribute to the stability and translational activity of Ty1i RNA through specific interactions with structural motifs in the RNA. Full article

(This article belongs to the Special Issue Recent Progress in Understanding the Mechanism and Consequences of Retrotransposon Movement)

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Review

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923 KiB

Open AccessReview

Type W Human Endogenous Retrovirus (HERV-W) Integrations and Their Mobilization by L1 Machinery: Contribution to the Human Transcriptome and Impact on the Host Physiopathology

by Nicole Grandi and Enzo Tramontano

Viruses 2017, 9(7), 162; https://doi.org/10.3390/v9070162 - 27 Jun 2017

Cited by 56 | Viewed by 15288

Abstract

Human Endogenous Retroviruses (HERVs) are ancient infection relics constituting ~8% of our DNA. While HERVs’ genomic characterization is still ongoing, impressive amounts of data have been obtained regarding their general expression across tissues. Among HERVs, one of the most studied is the W group, which is the sole HERV group specifically mobilized by the long interspersed element-1 (LINE-1) machinery, providing a source of novel insertions by retrotransposition of HERV-W processed pseudogenes, and comprising a member encoding a functional envelope protein coopted for human placentation. The HERV-W group has been intensively investigated for its putative role in several diseases, such as cancer, inflammation, and autoimmunity. Despite major interest in the link between HERV-W expression and human pathogenesis, no conclusive correlation has been demonstrated so far. In general, (i) the absence of a proper identification of the specific HERV-W sequences expressed in a given condition, and (ii) the lack of studies attempting to connect the various observations in the same experimental conditions are the major problems preventing the definitive assessment of the HERV-W impact on human physiopathology. In this review, we summarize the current knowledge on the HERV-W group presence within the human genome and its expression in physiological tissues as well as in the main pathological contexts. Full article

(This article belongs to the Special Issue Recent Progress in Understanding the Mechanism and Consequences of Retrotransposon Movement)

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378 KiB

Open AccessReview

The Role of Somatic L1 Retrotransposition in Human Cancers

by Emma C. Scott and Scott E. Devine

Viruses 2017, 9(6), 131; https://doi.org/10.3390/v9060131 - 31 May 2017

Cited by 67 | Viewed by 9865

Abstract

The human LINE-1 (or L1) element is a non-LTR retrotransposon that is mobilized through an RNA intermediate by an L1-encoded reverse transcriptase and other L1-encoded proteins. L1 elements remain actively mobile today and continue to mutagenize human genomes. Importantly, when new insertions disrupt gene function, they can cause diseases. Historically, L1s were thought to be active in the germline but silenced in adult somatic tissues. However, recent studies now show that L1 is active in at least some somatic tissues, including epithelial cancers. In this review, we provide an overview of these recent developments, and examine evidence that somatic L1 retrotransposition can initiate and drive tumorigenesis in humans. Recent studies have: (i) cataloged somatic L1 activity in many epithelial tumor types; (ii) identified specific full-length L1 source elements that give rise to somatic L1 insertions; and (iii) determined that L1 promoter hypomethylation likely plays an early role in the derepression of L1s in somatic tissues. A central challenge moving forward is to determine the extent to which L1 driver mutations can promote tumor initiation, evolution, and metastasis in humans. Full article

(This article belongs to the Special Issue Recent Progress in Understanding the Mechanism and Consequences of Retrotransposon Movement)

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241 KiB

Open AccessReview

Epigenetic Control of Human Endogenous Retrovirus Expression: Focus on Regulation of Long-Terminal Repeats (LTRs)

by Tara P. Hurst and Gkikas Magiorkinis

Viruses 2017, 9(6), 130; https://doi.org/10.3390/v9060130 - 31 May 2017

Cited by 94 | Viewed by 8594

Abstract

Transposable elements, including endogenous retroviruses (ERVs), comprise almost 45% of the human genome. This could represent a significant pathogenic burden but it is becoming more evident that many of these elements have a positive contribution to make to normal human physiology. In particular, the contributions of human ERVs (HERVs) to gene regulation and the expression of noncoding RNAs has been revealed with the help of new and emerging genomic technologies. HERVs have the common provirus structure of coding open reading frames (ORFs) flanked by two long-terminal repeats (LTRs). However, over the course of evolution and as a consequence of host defence mechanisms, most of the sequences contain INDELs, mutations or have been reduced to single LTRs by recombination. These INDELs and mutations reduce HERV activity. However, there is a trade-off for the host cells in that HERVs can provide beneficial sources of genetic variation but with this benefit comes the risk of pathogenic activity and spread within the genome. For example, the LTRs are of critical importance as they contain promoter sequences and can regulate not only HERV expression but that of human genes. This is true even when the LTRs are located in intergenic regions or are in antisense orientation to the rest of the gene. Uncontrolled, this promoter activity could disrupt normal gene expression or transcript processing (e.g., splicing). Thus, control of HERVs and particularly their LTRs is essential for the cell to manage these elements and this control is achieved at multiple levels, including epigenetic regulations that permit HERV expression in the germline but silence it in most somatic tissues. We will discuss some of the common epigenetic mechanisms and how they affect HERV expression, providing detailed discussions of HERVs in stem cell, placenta and cancer biology. Full article

(This article belongs to the Special Issue Recent Progress in Understanding the Mechanism and Consequences of Retrotransposon Movement)

1532 KiB

Open AccessReview

Mechanisms of LTR‐Retroelement Transposition: Lessons from Drosophila melanogaster

by Lidia Nefedova and Alexander Kim

Viruses 2017, 9(4), 81; https://doi.org/10.3390/v9040081 - 16 Apr 2017

Cited by 15 | Viewed by 7788

Abstract

Long terminal repeat (LTR) retrotransposons occupy a special place among all mobile genetic element families. The structure of LTR retrotransposons that have three open reading frames is identical to DNA forms of retroviruses that are integrated into the host genome. Several lines of evidence suggest that LTR retrotransposons share a common ancestry with retroviruses and thus are highly relevant to understanding mechanisms of transposition. Drosophila melanogaster is an exceptionally convenient model for studying the mechanisms of retrotransposon movement because many such elements in its genome are transpositionally active. Moreover, two LTRretrotransposons of D. melanogaster, gypsy and ZAM, have been found to have infectious properties and have been classified as errantiviruses. Despite numerous studies focusing on retroviral integration process, there is still no clear understanding of integration specificity in a target site. Most LTR retrotransposons non‐specifically integrate into a target site. Site‐specificity of integration at vertebrate retroviruses is rather relative. At the same time, sequence‐specific integration is the exclusive property of errantiviruses and their derivatives with two open reading frames. The possible basis for the errantivirus integration specificity is discussed in the present review. Full article

(This article belongs to the Special Issue Recent Progress in Understanding the Mechanism and Consequences of Retrotransposon Movement)

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Open AccessReview

Protein-Coding Genes’ Retrocopies and Their Functions

by Magdalena Regina Kubiak and Izabela Makałowska

Viruses 2017, 9(4), 80; https://doi.org/10.3390/v9040080 - 13 Apr 2017

Cited by 49 | Viewed by 9998

Abstract

Transposable elements, often considered to be not important for survival, significantly contribute to the evolution of transcriptomes, promoters, and proteomes. Reverse transcriptase, encoded by some transposable elements, can be used in trans to produce a DNA copy of any RNA molecule in the cell. The retrotransposition of protein-coding genes requires the presence of reverse transcriptase, which could be delivered by either non-long terminal repeat (non-LTR) or LTR transposons. The majority of these copies are in a state of “relaxed” selection and remain “dormant” because they are lacking regulatory regions; however, many become functional. In the course of evolution, they may undergo subfunctionalization, neofunctionalization, or replace their progenitors. Functional retrocopies (retrogenes) can encode proteins, novel or similar to those encoded by their progenitors, can be used as alternative exons or create chimeric transcripts, and can also be involved in transcriptional interference and participate in the epigenetic regulation of parental gene expression. They can also act in trans as natural antisense transcripts, microRNA (miRNA) sponges, or a source of various small RNAs. Moreover, many retrocopies of protein-coding genes are linked to human diseases, especially various types of cancer. Full article

(This article belongs to the Special Issue Recent Progress in Understanding the Mechanism and Consequences of Retrotransposon Movement)

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863 KiB

Open AccessReview

Cross-Regulation between Transposable Elements and Host DNA Replication

by Mikel Zaratiegui

Viruses 2017, 9(3), 57; https://doi.org/10.3390/v9030057 - 21 Mar 2017

Cited by 11 | Viewed by 6871

Abstract

Transposable elements subvert host cellular functions to ensure their survival. Their interaction with the host DNA replication machinery indicates that selective pressures lead them to develop ancestral and convergent evolutionary adaptations aimed at conserved features of this fundamental process. These interactions can shape [...] Read more.

(This article belongs to the Special Issue Recent Progress in Understanding the Mechanism and Consequences of Retrotransposon Movement)

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1786 KiB

Open AccessReview

Reverse Transcription in the Saccharomyces cerevisiae Long-Terminal Repeat Retrotransposon Ty3

by Jason W. Rausch, Jennifer T. Miller and Stuart F. J. Le Grice

Viruses 2017, 9(3), 44; https://doi.org/10.3390/v9030044 - 15 Mar 2017

Cited by 4 | Viewed by 6103

Abstract

Converting the single-stranded retroviral RNA into integration-competent double-stranded DNA is achieved through a multi-step process mediated by the virus-coded reverse transcriptase (RT). With the exception that it is restricted to an intracellular life cycle, replication of the Saccharomyces cerevisiae long terminal repeat (LTR)-retrotransposon Ty3 genome is guided by equivalent events that, while generally similar, show many unique and subtle differences relative to the retroviral counterparts. Until only recently, our knowledge of RT structure and function was guided by a vast body of literature on the human immunodeficiency virus (HIV) enzyme. Although the recently-solved structure of Ty3 RT in the presence of an RNA/DNA hybrid adds little in terms of novelty to the mechanistic basis underlying DNA polymerase and ribonuclease H activity, it highlights quite remarkable topological differences between retroviral and LTR-retrotransposon RTs. The theme of overall similarity but distinct differences extends to the priming mechanisms used by Ty3 RT to initiate (−) and (+) strand DNA synthesis. The unique structural organization of the retrotransposon enzyme and interaction with its nucleic acid substrates, with emphasis on polypurine tract (PPT)-primed initiation of (+) strand synthesis, is the subject of this review. Full article

(This article belongs to the Special Issue Recent Progress in Understanding the Mechanism and Consequences of Retrotransposon Movement)

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