Review

Authors: Carlos Mendez-Dorantes, Kathleen H Burns

Long interspersed element 1 (LINE-1) is the only protein-coding transposon that is active in humans. LINE-1 propagates in the genome using RNA intermediates via retrotransposition. This activity has resulted in LINE-1 sequences occupying approximately one-fifth of our genome. Although most copies of LINE-1 are immobile, ∼100 copies are retrotransposition-competent. Retrotransposition is normally limited via epigenetic silencing, DNA repair, and other host defense mechanisms. In contrast, LINE-1 overexpression and retrotransposition are hallmarks of cancers. Here, we review mechanisms of LINE-1 regulation and how LINE-1 may promote genetic heterogeneity in tumors. Finally, we discuss therapeutic strategies to exploit LINE-1 biology in cancers.

Topics: Humans; Long Interspersed Nucleotide Elements; Neoplasms; RNA; Proteins; Epigenesis, Genetic

PubMed: 38092519
DOI: 10.1101/gad.351051.123

Authors: Zhengyi Zhen, Yu Chen, Haiyan Wang...

Cyclic GMP-AMP synthase (cGAS), initially identified as a cytosolic DNA sensor, detects DNA fragments to trigger an innate immune response. Recently, accumulating evidence reveals the presence of cGAS within the nucleus. However, the biological functions of nuclear cGAS are not fully understood. Here, we demonstrate that nuclear cGAS represses LINE-1 (L1) retrotransposition to preserve genome integrity in human cells. Mechanistically, the E3 ligase TRIM41 interacts with and ubiquitinates ORF2p to influence its stability, and cGAS enhances the association of ORF2p with TRIM41, thereby promoting TRIM41-mediated ORF2p degradation and the suppression of L1 retrotransposition. In response to DNA damage, cGAS is phosphorylated at serine residues 120 and 305 by CHK2, which promotes cGAS-TRIM41 association, facilitating TRIM41-mediated ORF2p degradation. Moreover, we show that nuclear cGAS mediates the repression of L1 retrotransposition in senescent cells induced by DNA damage agents. We also identify several cancer-associated cGAS mutations that abolish the suppressive effect on L1 retrotransposition by disrupting the CHK2-cGAS-TRIM41-ORF2p regulatory axis. Together, these findings indicate that nuclear cGAS exhibits an inhibitory function in L1 retrotransposition which could provide avenues for future interventions in both aging and tumorigenesis.

Topics: Humans; DNA; Long Interspersed Nucleotide Elements; Nucleotidyltransferases; Ubiquitin-Protein Ligases; Ubiquitination

PubMed: 38086852
DOI: 10.1038/s41467-023-43001-y

Authors: Chang Hyun Nam, Jeonghwan Youk, Jeong Yeon Kim...

Throughout an individual's lifetime, genomic alterations accumulate in somatic cells. However, the mutational landscape induced by retrotransposition of long interspersed nuclear element-1 (L1), a widespread mobile element in the human genome, is poorly understood in normal cells. Here we explored the whole-genome sequences of 899 single-cell clones established from three different cell types collected from 28 individuals. We identified 1,708 somatic L1 retrotransposition events that were enriched in colorectal epithelium and showed a positive relationship with age. Fingerprinting of source elements showed 34 retrotransposition-competent L1s. Multidimensional analysis demonstrated that (1) somatic L1 retrotranspositions occur from early embryogenesis at a substantial rate, (2) epigenetic on/off of a source element is preferentially determined in the early organogenesis stage, (3) retrotransposition-competent L1s with a lower population allele frequency have higher retrotransposition activity and (4) only a small fraction of L1 transcripts in the cytoplasm are finally retrotransposed in somatic cells. Analysis of matched cancers further suggested that somatic L1 retrotransposition rate is substantially increased during colorectal tumourigenesis. In summary, this study illustrates L1 retrotransposition-induced somatic mosaicism in normal cells and provides insights into the genomic and epigenomic regulation of transposable elements over the human lifetime.

Topics: Humans; Carcinogenesis; Colorectal Neoplasms; DNA Transposable Elements; Genomics; Long Interspersed Nucleotide Elements; Retroelements; Aging; Gene Frequency; Mosaicism; Epigenomics; Genome, Human; Colon; Intestinal Mucosa; Embryonic Development

PubMed: 37165195
DOI: 10.1038/s41586-023-06046-z

Authors: Jiwei Ding, Shujie Wang, Qipeng Liu...

Long interspersed element 1 (LINE-1) is the only currently known active autonomous transposon in humans, and its retrotransposition may cause deleterious effects on the structure and function of host cell genomes and result in sporadic genetic diseases. Host cells therefore developed defense strategies to restrict LINE-1 mobilization. In this study, we demonstrated that IFN-inducible Schlafen5 (SLFN5) inhibits LINE-1 retrotransposition. Mechanistic studies revealed that SLFN5 interrupts LINE-1 ribonucleoprotein particle (RNP) formation, thus diminishing nuclear entry of the LINE-1 RNA template and subsequent LINE-1 cDNA production. The ability of SLFN5 to bind to LINE-1 RNA and the involvement of the helicase domain of SLFN5 in its inhibitory activity suggest a mechanism that SLFN5 binds to LINE-1 RNA followed by dissociation of ORF1p through its helicase activity, resulting in impaired RNP formation. These data highlight a new mechanism of host cells to restrict LINE-1 mobilization.

PubMed: 37810251
DOI: 10.1016/j.isci.2023.107968

Authors: Rocio Enriquez-Gasca, Poppy A Gould, Hale Tunbak...

Endogenous retroviruses (ERVs) have rewired host gene networks. To explore the origins of co-option, we employed an active murine ERV, IAPEz, and an embryonic stem cell (ESC) to neural progenitor cell (NPC) differentiation model. Transcriptional silencing via TRIM28 maps to a 190 bp sequence encoding the intracisternal A-type particle (IAP) signal peptide, which confers retrotransposition activity. A subset of "escapee" IAPs (∼15%) exhibits significant genetic divergence from this sequence. Canonical repressed IAPs succumb to a previously undocumented demarcation by H3K9me3 and H3K27me3 in NPCs. Escapee IAPs, in contrast, evade repression in both cell types, resulting in their transcriptional derepression, particularly in NPCs. We validate the enhancer function of a 47 bp sequence within the U3 region of the long terminal repeat (LTR) and show that escapee IAPs convey an activating effect on nearby neural genes. In sum, co-opted ERVs stem from genetic escapees that have lost vital sequences required for both TRIM28 restriction and autonomous retrotransposition.

Topics: Animals; Mice; Cell Differentiation; Embryonic Stem Cells; Endogenous Retroviruses; Histones; Tripartite Motif-Containing Protein 28; Terminal Repeat Sequences

PubMed: 37294634
DOI: 10.1016/j.celrep.2023.112625

Review

Authors: Gabriela O Bodea, Eleanor G Z McKelvey, Geoffrey J Faulkner...

Over the past decade, major discoveries in retrotransposon biology have depicted the neural genome as a dynamic structure during life. In particular, the retrotransposon LINE-1 (L1) has been shown to be transcribed and mobilized in the brain. Retrotransposition in the developing brain, as well as during adult neurogenesis, provides a milieu in which neural diversity can arise. Dysregulation of retrotransposon activity may also contribute to neurological disease. Here, we review recent reports of retrotransposon activity in the brain, and discuss the temporal nature of retrotransposition and its regulation in neural cells in response to stimuli. We also put forward hypotheses regarding the significance of retrotransposons for brain development and neurological function, and consider the potential implications of this phenomenon for neuropsychiatric and neurodegenerative conditions.

Topics: Brain; Genome, Human; Humans; Mosaicism; Neurogenesis; Neurons; Retroelements

PubMed: 30021882
DOI: 10.1098/rsob.180074

Authors: Ahmad Luqman-Fatah, Yuzo Watanabe, Kazuko Uno...

Some interferon stimulated genes (ISGs) encode proteins that inhibit LINE-1 (L1) retrotransposition. Here, we use immunoprecipitation followed by liquid chromatography-tandem mass spectrometry to identify proteins that associate with the L1 ORF1-encoded protein (ORF1p) in ribonucleoprotein particles. Three ISG proteins that interact with ORF1p inhibit retrotransposition: HECT and RLD domain containing E3 ubiquitin-protein ligase 5 (HERC5); 2'-5'-oligoadenylate synthetase-like (OASL); and helicase with zinc finger 2 (HELZ2). HERC5 destabilizes ORF1p, but does not affect its cellular localization. OASL impairs ORF1p cytoplasmic foci formation. HELZ2 recognizes sequences and/or structures within the L1 5'UTR to reduce L1 RNA, ORF1p, and ORF1p cytoplasmic foci levels. Overexpression of WT or reverse transcriptase-deficient L1s lead to a modest induction of IFN-α expression, which is abrogated upon HELZ2 overexpression. Notably, IFN-α expression is enhanced upon overexpression of an ORF1p RNA binding mutant, suggesting ORF1p binding might protect L1 RNA from "triggering" IFN-α induction. Thus, ISG proteins can inhibit retrotransposition by different mechanisms.

Topics: Humans; Interferon Type I; Long Interspersed Nucleotide Elements; Proteins; RNA; RNA Helicases; RNA-Directed DNA Polymerase

PubMed: 36639706
DOI: 10.1038/s41467-022-35757-6

Review

Authors: Muhammad Jahangir, Li Li, Jian-Song Zhou...

The long interspersed nuclear elements 1 (LINE-1/L1s) are the only active autonomous retrotransposons found in humans which can integrate anywhere in the human genome. They can expand the genome and thus bring good or bad effects to the host cells which really depends on their integration site and associated polymorphism. LINE-1 retrotransposition has been found participating in various neurological disorders such as autism spectrum disorder, Alzheimer's disease, major depression disorder, post-traumatic stress disorder and schizophrenia. Despite the recent progress, the roles and pathological mechanism of LINE-1 retrotransposition in schizophrenia and its heritable risks, particularly, contribution to "missing heritability" are yet to be determined. Therefore, this review focuses on the potentially etiological roles of L1s in the development of schizophrenia, possible therapeutic choices and unaddressed questions in order to shed lights on the future research.

PubMed: 35832186
DOI: 10.3389/fgene.2022.878508

Review

Authors: Eirini Mastora, Antonia Christodoulaki, Kyriaki Papageorgiou...

Retroelements are genetic mobile elements, expressed during male and female gamete differentiation. Retrotransposons are normally regulated by the methylation machinery, chromatin modifications, non-coding RNAs, and transcription factors, while retrotransposition control is of vital importance in cellular proliferation and differentiation process. Retrotransposition requires a transcription step, by a cellular RNA polymerase, followed by reverse transcription of an RNA intermediate to cDNA and its integration into a new genomic locus. Long interspersed elements (LINEs), human endogenous retroviruses (HERVs), short interspersed elements (SINEs) and SINE-VNTR-Alu elements (SVAs) constitute about half of the human genome, play a crucial role in genome organization, structure and function and interfere with several biological procedures. In this mini review, we discuss recent data regarding retroelement expression (LINE-1, HERVK-10, SVA and VL30) and retrotransposition events in mammalian oocytes and spermatozoa, as well as the importance of their impact on human and mouse preimplantation embryo development.

Topics: Alu Elements; Animals; Female; Humans; Long Interspersed Nucleotide Elements; Male; Mice; Oocytes; Retroelements; Short Interspersed Nucleotide Elements

PubMed: 34182464
DOI: 10.21873/invivo.12458

Review

Authors: M Nabuan Naufer, Anthony V Furano, Mark C Williams...

Long interspersed nuclear element 1 (LINE-1 or L1) is the dominant retrotransposon in mammalian genomes. L1 encodes two proteins ORF1p and ORF2p that are required for retrotransposition. ORF2p functions as the replicase. ORF1p is a coiled coil-mediated trimeric, high affinity RNA binding protein that packages its full- length coding transcript into an ORF2p-containing ribonucleoprotein (RNP) complex, the retrotransposition intermediate. ORF1p also is a nucleic acid chaperone that presumably facilitates the proposed nucleic acid remodeling steps involved in retrotransposition. Although detailed mechanistic understanding of ORF1p function in this process is lacking, recent studies showed that the rate at which ORF1p can form stable nucleic acid-bound oligomers in vitro is positively correlated with formation of an active L1 RNP as assayed in vivo using a cell culture-based retrotransposition assay. This rate was sensitive to minor amino acid changes in the coiled coil domain, which had no effect on nucleic acid chaperone activity. Additional studies linking the complex nucleic acid binding properties to the conformational changes of the protein are needed to understand how ORF1p facilitates retrotransposition.

Topics: Animals; Binding Sites; DNA; DNA-Binding Proteins; Humans; Kinetics; Long Interspersed Nucleotide Elements; Open Reading Frames

PubMed: 29596909
DOI: 10.1016/j.semcdb.2018.03.019