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Proceedings of the National Academy of... Dec 2022Activation of endogenous retrotransposons frequently occurs in cancer cells and contributes to tumor genomic instability. To test whether inhibition of...
Activation of endogenous retrotransposons frequently occurs in cancer cells and contributes to tumor genomic instability. To test whether inhibition of retrotranspositions has an anticancer effect, we used treatment with the nucleoside reverse transcriptase inhibitor (NRTI) stavudine (STV) in mouse cancer models, MMTV-HER2/Neu and Th-MYCN, that spontaneously develop breast cancer and neuroblastoma, respectively. In both cases, STV in drinking water did not affect tumor incidence nor demonstrate direct antitumor effects. However, STV dramatically extended progression-free survival in both models following an initial complete response to chemotherapy. To approach the mechanism underlying this phenomenon, we analyzed the effect of NRTI on the selection of treatment-resistant variants in tumor cells in culture. Cultivation of mouse breast carcinoma 4T1 in the presence of STV dramatically reduced the frequency of cells capable of surviving treatment with anticancer drugs. Global transcriptome analysis demonstrated that the acquisition of drug resistance by 4T1 cells was accompanied by an increase in the constitutive activity of interferon type I and NF-κB pathways and an elevated expression of LINE-1 elements, which are known to induce inflammatory responses via their products of reverse transcription. Treatment with NRTI reduced NF-κB activity and reverted drug resistance. Furthermore, the inducible expression of LINE-1 stimulated inflammatory response and increased the frequency of drug-resistant variants in a tumor cell population. These results indicate a mechanism by which retrotransposon desilencing can stimulate tumor cell survival during treatment and suggest reverse transcriptase inhibition as a potential therapeutic approach for targeting the development of drug-resistant cancers.
Topics: Animals; Mice; Reverse Transcriptase Inhibitors; Retroelements; NF-kappa B; Drug Resistance, Neoplasm; Long Interspersed Nucleotide Elements
PubMed: 36449545
DOI: 10.1073/pnas.2213146119 -
Genes & Genetic Systems Jan 2020The majority of eukaryotic genomes contain a large fraction of repetitive sequences that primarily originate from transpositional bursts of transposable elements (TEs).... (Review)
Review
The majority of eukaryotic genomes contain a large fraction of repetitive sequences that primarily originate from transpositional bursts of transposable elements (TEs). Repbase serves as a database for eukaryotic repetitive sequences and has now become the largest collection of eukaryotic TEs. During the development of Repbase, many new superfamilies/lineages of TEs, which include Helitron, Polinton, Ginger and SINEU, were reported. The unique composition of protein domains and DNA motifs in TEs sometimes indicates novel mechanisms of transposition, replication, anti-suppression or proliferation. In this review, our current understanding regarding the diversity of eukaryotic TEs in sequence, protein domain composition and structural hallmarks is introduced and summarized, based on the classification system implemented in Repbase. Autonomous eukaryotic TEs can be divided into two groups: Class I TEs, also called retrotransposons, and Class II TEs, or DNA transposons. Long terminal repeat (LTR) retrotransposons, including endogenous retroviruses, non-LTR retrotransposons, tyrosine recombinase retrotransposons and Penelope-like elements, are well accepted groups of autonomous retrotransposons. They share reverse transcriptase for replication but are distinct in the catalytic components responsible for integration into the host genome. Similarly, at least three transposition machineries have been reported in eukaryotic DNA transposons: DDD/E transposase, tyrosine recombinase and HUH endonuclease combined with helicase. Among these, TEs with DDD/E transposase are dominant and are classified into 21 superfamilies in Repbase. Non-autonomous TEs are either simple derivatives generated by internal deletion, or are composed of several units that originated independently.
Topics: Computational Biology; DNA Transposable Elements; Eukaryota; Genetic Variation; Protein Domains; Retroelements
PubMed: 30416149
DOI: 10.1266/ggs.18-00024 -
ELife Apr 2021Bacteria carry antibiotic resistant genes on movable sections of DNA that allow them to select the relevant genes on demand.
Bacteria carry antibiotic resistant genes on movable sections of DNA that allow them to select the relevant genes on demand.
Topics: Anti-Bacterial Agents; Bacteria; Drug Resistance, Microbial; Integrons
PubMed: 33820602
DOI: 10.7554/eLife.68070 -
Proceedings of the National Academy of... Jun 2023Ribosomal DNA (rDNA) loci contain hundreds of tandemly repeated copies of ribosomal RNA genes needed to support cellular viability. This repetitiveness makes it highly...
Ribosomal DNA (rDNA) loci contain hundreds of tandemly repeated copies of ribosomal RNA genes needed to support cellular viability. This repetitiveness makes it highly susceptible to copy number (CN) loss due to intrachromatid recombination between rDNA copies, threatening multigenerational maintenance of rDNA. How this threat is counteracted to avoid extinction of the lineage has remained unclear. Here, we show that the rDNA-specific retrotransposon R2 is essential for restorative rDNA CN expansion to maintain rDNA loci in the Drosophila male germline. The depletion of R2 led to defective rDNA CN maintenance, causing a decline in fecundity over generations and eventual extinction. We find that double-stranded DNA breaks created by the R2 endonuclease, a feature of R2's rDNA-specific retrotransposition, initiate the process of rDNA CN recovery, which relies on homology-dependent repair of the DNA break at rDNA copies. This study reveals that an active retrotransposon provides an essential function for its host, contrary to transposable elements' reputation as entirely selfish. These findings suggest that benefiting host fitness can be an effective selective advantage for transposable elements to offset their threat to the host, which may contribute to retrotransposons' widespread success throughout taxa.
Topics: Animals; Retroelements; DNA, Ribosomal; Drosophila; DNA Transposable Elements
PubMed: 37252996
DOI: 10.1073/pnas.2221613120 -
Cell Host & Microbe Jan 2023Phage-inducible chromosomal islands (PICIs) steal structural proteins from helper phages. In two related studies, Penadés and coworkers reveal that PICIs are not...
Phage-inducible chromosomal islands (PICIs) steal structural proteins from helper phages. In two related studies, Penadés and coworkers reveal that PICIs are not parasites but mutualists. Some PICIs mobilize defense systems that restrict niche competitors, while other PICIs encode their own capsids and steal helper phage tails without affecting their fitness.
Topics: Genomic Islands; Bacteriophages; Capsid
PubMed: 36634621
DOI: 10.1016/j.chom.2022.12.008 -
Biomolecules Apr 2023Neurofibromatosis type 1 is an autosomal-dominant condition caused by gene inactivation. Clinical diagnosis is corroborated by genetic tests on gDNA and cDNA, which are...
Neurofibromatosis type 1 is an autosomal-dominant condition caused by gene inactivation. Clinical diagnosis is corroborated by genetic tests on gDNA and cDNA, which are inconclusive in approximately 3-5% of cases. Genomic DNA approaches may overlook splicing-affecting intronic variants and structural rearrangements, especially in regions enriched in repetitive sequences. On the other hand, while cDNA-based methods provide direct information about the effect of a variant on gene transcription, they are hampered by non-sense-mediated mRNA decay and skewed or monoallelic expression. Moreover, analyses on gene transcripts in some patients do not allow tracing back to the causative event, which is crucial for addressing genetic counselling, prenatal monitoring, and developing targeted therapies. We report on a familial NF1, caused by an insertion of a partial LINE-1 element inside intron 15, leading to exon 15 skipping. Only a few cases of LINE-1 insertion have been reported so far, hampering gDNA studies because of their size. Often, they result in exon skipping, and their recognition of cDNA may be difficult. A combined approach, based on Optical Genome Mapping, WGS, and cDNA studies, enabled us to detect the LINE-1 insertion and test its effects. Our results improve knowledge of the NF1 mutational spectrum and highlight the importance of custom-built approaches in undiagnosed patients.
Topics: Pregnancy; Female; Humans; Neurofibromatosis 1; Introns; DNA, Complementary; Long Interspersed Nucleotide Elements; Mutation
PubMed: 37238595
DOI: 10.3390/biom13050725 -
PloS One 2023LINE-1 is an active transposable element encoding proteins capable of inserting host gene retrocopies, resulting in retro-copy number variants (retroCNVs) between...
LINE-1 is an active transposable element encoding proteins capable of inserting host gene retrocopies, resulting in retro-copy number variants (retroCNVs) between individuals. Here, we performed retroCNV discovery using 86 equids and identified 437 retrocopy insertions. Only 5 retroCNVs were shared between horses and other equids, indicating that the majority of retroCNVs inserted after the species diverged. A large number (17-35 copies) of segmentally duplicated Ligand Dependent Nuclear Receptor Corepressor Like (LCORL) retrocopies were present in all equids but absent from other extant perissodactyls. The majority of LCORL transcripts in horses and donkeys originate from the retrocopies. The initial LCORL retrotransposition occurred 18 million years ago (17-19 95% CI), which is coincident with the increase in body size, reduction in digit number, and changes in dentition that characterized equid evolution. Evolutionary conservation of the LCORL retrocopy segmental amplification in the Equidae family, high expression levels and the ancient timeline for LCORL retrotransposition support a functional role for this structural variant.
Topics: Animals; Horses; Long Interspersed Nucleotide Elements; Equidae; DNA Transposable Elements; Proteins
PubMed: 37289743
DOI: 10.1371/journal.pone.0286861 -
International Journal of Molecular... Sep 2023This review investigates the intricate role of human endogenous retroviruses (HERVs) in cancer development and progression, explicitly focusing on HERV-K (HML-2). This... (Review)
Review
This review investigates the intricate role of human endogenous retroviruses (HERVs) in cancer development and progression, explicitly focusing on HERV-K (HML-2). This paper sheds light on the latest research advancements and potential treatment strategies by examining the historical context of HERVs and their involvement in critical biological processes such as embryonic development, immune response, and disease progression. This review covers computational modeling for drug-target binding assessment, systems biology modeling for simulating HERV-K viral cargo dynamics, and using antiviral drugs to combat HERV-induced diseases. The findings presented in this review contribute to our understanding of HERV-mediated disease mechanisms and provide insights into future therapeutic approaches. They emphasize why HERV-K holds significant promise as a biomarker and a target.
Topics: Humans; Endogenous Retroviruses; Neoplasms; Tumor Virus Infections
PubMed: 37834078
DOI: 10.3390/ijms241914631 -
Philosophical Transactions of the Royal... Oct 2022Horizontal gene transfer (HGT) drives microbial adaptation but is often under the control of mobile genetic elements (MGEs) whose interests are not necessarily aligned... (Review)
Review
Horizontal gene transfer (HGT) drives microbial adaptation but is often under the control of mobile genetic elements (MGEs) whose interests are not necessarily aligned with those of their hosts. In general, transfer is costly to the donor cell while potentially beneficial to the recipients. The diversity and plasticity of cell-MGEs interactions, and those among MGEs, result in complex evolutionary processes where the source, or even the existence of selection for maintaining a function in the genome, is often unclear. For example, MGE-driven HGT depends on cell envelope structures and defense systems, but many of these are transferred by MGEs themselves. MGEs can spur periods of intense gene transfer by increasing their own rates of horizontal transmission upon communicating, eavesdropping, or sensing the environment and the host physiology. This may result in high-frequency transfer of host genes unrelated to the MGE. Here, we review how MGEs drive HGT and how their transfer mechanisms, selective pressures and genomic traits affect gene flow, and therefore adaptation, in microbial populations. The encoding of many adaptive niche-defining microbial traits in MGEs means that intragenomic conflicts and alliances between cells and their MGEs are key to microbial functional diversification. This article is part of a discussion meeting issue 'Genomic population structures of microbial pathogens'.
Topics: Biological Evolution; Gene Transfer, Horizontal; Interspersed Repetitive Sequences
PubMed: 35989606
DOI: 10.1098/rstb.2021.0234 -
Trends in Genetics : TIG Dec 2019Our recent ability to sequence entire genomes, along with all of their transcribed RNAs, has led to the surprising finding that only ∼1% of the human genome is used to... (Review)
Review
Our recent ability to sequence entire genomes, along with all of their transcribed RNAs, has led to the surprising finding that only ∼1% of the human genome is used to encode proteins. This finding has led to vigorous debate over the functional importance of the transcribed but untranslated portions of the genome. Currently, scientists tend to assume coding genes are functional until proven not to be, while the opposite is true for noncoding genes. This review takes a new look at the evidence for and against widespread noncoding gene functionality. We focus in particular on long noncoding RNA (noncoding RNAs longer than 200 nucleotides) genes and their 'junk' associates, transposable elements, and satellite repeats. Taken together, the suggestion put forward is that more of this junk DNA may be functional than nonfunctional and that noncoding RNAs and transposable elements act symbiotically to drive evolution.
Topics: Animals; DNA, Intergenic; Evolution, Molecular; Genetic Association Studies; Genome; Genomics; Humans; Interspersed Repetitive Sequences; Phenotype; RNA, Long Noncoding; Spermatogenesis
PubMed: 31662190
DOI: 10.1016/j.tig.2019.09.006