An update on post‐transcriptional regulation of retrotransposons

Warkocki, Zbigniew

doi:10.1002/1873-3468.14551

Cited by 9 publications

(3 citation statements)

References 272 publications

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“…Mael -/spermatocytes develop cytoplasmic bodies enriched in ORF1p, L1 RNA, and ribosomes Meiotic male germ cells (spermatocytes) of Mael -/mice overexpress L1 and develop prominent ORF1p-positive cytoplasmic bodies packed with ~25 nm electron-dense particles [45]. This work will refer to these structures as LBs for LINE-1 Bodies (a term also suggested recently by others [54]). In EM images, LBs first appear as submicron cytoplasmic aggregates (Fig 1A , 1B, 1A' and 1B'), reminiscent of ORF1p aggregates occurring in wild-type (WT) spermatocytes (S1 Fig) . In Mael -/mice, smaller LBs appear to fuse, forming large LBs that sometimes associate with membranes (Fig 1C -1E).…”

Section: Resultsmentioning

confidence: 88%

Retrotransposon LINE-1 bodies in the cytoplasm of piRNA-deficient mouse spermatocytes: Ribonucleoproteins overcoming the integrated stress response

2023

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Transposable elements (TE) are mobile DNA sequences whose excessive proliferation endangers the host. Although animals have evolved robust TE-targeting defenses, including Piwi-interacting (pi)RNAs, retrotransposon LINE-1 (L1) still thrives in humans and mice. To gain insights into L1 endurance, we characterized L1 Bodies (LBs) and ORF1p complexes in germ cells of piRNA-deficient Maelstrom null mice. We report that ORF1p interacts with TE RNAs, genic mRNAs, and stress granule proteins, consistent with earlier studies. We also show that ORF1p associates with the CCR4-NOT deadenylation complex and PRKRA, a Protein Kinase R factor. Despite ORF1p interactions with these negative regulators of RNA expression, the stability and translation of LB-localized mRNAs remain unchanged. To scrutinize these findings, we studied the effects of PRKRA on L1 in cultured cells and showed that it elevates ORF1p levels and L1 retrotransposition. These results suggest that ORF1p-driven condensates promote L1 propagation, without affecting the metabolism of endogenous RNAs.

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Section: Resultsmentioning

confidence: 88%

Retrotransposon LINE-1 bodies in the cytoplasm of piRNA-deficient mouse spermatocytes: Ribonucleoproteins overcoming the integrated stress response

2023

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“…The poorer survival HERV-H1 and HERV-H3 subgroups had more highly expressed genes than the better survival subgroups (HERV-L and HERV-H2). These findings contradict the function of HERV activation restriction and KZFP genes, which are expressed in normal cells to suppress HERV expression [18,79,81]. The dysregulation of HERV activation restriction genes has also been found in other cancers, such as the overexpression of TET1, TET3, and APOBEC3B but downregulation of APOBEC3C, 3G, 3D, 3H, and C2 in prostate cancer, and different cancers may involve different activation restriction genes [9,10].…”

Section: Discussionmentioning

confidence: 88%

Comprehensive Analysis and Drug Modulation of Human Endogenous Retrovirus in Hepatocellular Carcinomas

Chang

Hsu

Chung

et al. 2023

Cancers

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Background: Human endogenous retroviruses (HERVs) play an important role in the development of cancer and many diseases. Here, we comprehensively explored the impact of HERVs on hepatocellular carcinomas (HCCs). Methods: We employed Telescope to identify HERVs and quantify their expression in the total RNA sequencing data obtained from 254 HCC samples, comprising 254 tumor tissues and 34 matched normal tissues. Results: In total, 3357 locus-specific activations of HERVs were differentially expressed, and 180 were correlated with patient survival. Using these 180 HERVs for classification, we found four subgroups with survival correlation. Higher expression levels of the 180 HERVs were correlated with poorer survival, while age, AFP, some mutations, and copy and structural variants differed among subgroups. The differential expression of host genes in high expression of these 180 HERVs primarily involved the activation of pathways related to immunity and infection, lipid and atherosclerosis, MAPK and NF-kB signaling, and cytokine–cytokine receptor interactions. Conversely, there was a suppression of pathways associated with RNA processing, including nucleocytoplasmic transport, surveillance and ribosome biogenesis, and transcriptional misregulation in cancer pathways. Almost all genes involved in HERV activation restriction, KRAB zinc finger proteins, RNA nucleocytoplasmic transport, stemness, HLA and antigen processing and presentation, and immune checkpoints were overexpressed in cancerous tissues, and many over-expressed HERV-related nearby genes were correlated with high HERV activation and poor survival. Twenty-three immune and stromal cells showed higher expression in non-cancerous than cancerous tissues, and seven were correlated with HERV activation. Small-molecule modulation of alternative splicing (AS) altered the expression of survival-related HERVs and their activation-related genes, as well as nearby genes. Conclusion: Comprehensive and integrated approaches for evaluating HERV expression and their correlation with specific pathways have the potential to provide new companion diagnostics and therapeutic strategies for HCC.

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“…Thus, the life cycle of L1 resembles that of retroviruses because it involves a reverse transcription step. A full-length L1 is approximately 6 kb in length and comprises a 5 untranslated region (UTR), two ORFs encoding ORF1p and ORF2p, and a 3 UTR followed by a poly(A) tail (Figure 1B) [14][15][16][17]. Typically, L1 is flanked by short stretches (between 6 and 20 bp) of identical host DNA, called TSDs.…”

Section: Introductionmentioning

confidence: 99%

Roles of Human Endogenous Retroviruses and Endogenous Virus-Like Elements in Cancer Development and Innate Immunity

Katoh,

Honda

2023

Biomolecules

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Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections in the host genome. Although mutations and silencing mechanisms impair their original role in viral replication, HERVs are believed to play roles in various biological processes. Long interspersed nuclear elements (LINEs) are non-LTR retrotransposons that have a lifecycle resembling that of retroviruses. Although LINE expression is typically silenced in somatic cells, it also contributes to various biological processes. The aberrant expression of HERVs and LINEs is closely associated with the development of cancer and/or immunological diseases, suggesting that they are integrated into various pathways related to the diseases. HERVs/LINEs control gene expression depending on the context as promoter/enhancer elements. Some RNAs and proteins derived from HERVs/LINEs have oncogenic potential, whereas others stimulate innate immunity. Non-retroviral endogenous viral elements (nrEVEs) are a novel type of virus-like element in the genome. nrEVEs may also be involved in host immunity. This article provides a current understanding of how these elements impact cellular physiology in cancer development and innate immunity, and provides perspectives for future studies.

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An update on post‐transcriptional regulation of retrotransposons

Cited by 9 publications

References 272 publications

Retrotransposon LINE-1 bodies in the cytoplasm of piRNA-deficient mouse spermatocytes: Ribonucleoproteins overcoming the integrated stress response

Retrotransposon LINE-1 bodies in the cytoplasm of piRNA-deficient mouse spermatocytes: Ribonucleoproteins overcoming the integrated stress response

Comprehensive Analysis and Drug Modulation of Human Endogenous Retrovirus in Hepatocellular Carcinomas

Roles of Human Endogenous Retroviruses and Endogenous Virus-Like Elements in Cancer Development and Innate Immunity

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