Heteromeric RNP Assembly at LINEs Controls Lineage-Specific RNA Processing

Attig, Jan; Federico, Antonella; Gooding, Clare; Chakrabarti, Anob M.; Singh, Aarti; Haberman, Nejc; Zagalak, Julian A.; Emmett, Warren; Smith, Christopher W.; Luscombe, Nicholas M.; Ule, Jernej

doi:10.1016/j.cell.2018.07.001

Cited by 139 publications

(176 citation statements)

References 63 publications

(87 reference statements)

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“…Recently, a CRISPR screen has revealed many positive and negative regulators of active L1 . Screening of RNA interactome data from crosslinking and immunoprecipitation of RBPs has identified dozens of RBPs that interact with RDEs . A few of the RBPs that restrict L1 retrotransposition, are well‐characterized and general mRNA surveillance factors (MOV10, UPF1, TUT4/7, RNASEH2).…”

Section: Many Rna‐binding Factors Bind Retrotransposons To Regulate Tmentioning

confidence: 99%

“…It has become evident that many RBPs recognize specific sequence or structural motifs formed by the different RDE families, and thereby efficiently protect host gene expression by reducing recognition of RNA processing sites within them. Prominent examples of RBP:RDE interactions are discussed here in detail, and include control of Alu RDEs by HNRNPC/U2AF65, ADAR/DHX9 and STAU1/PKR, and repression of LINE‐derived exons by MATR3/PTBP1 …”

Section: Many Rbps Bind To Intronic Rdes To Regulate Their Rna Procesmentioning

confidence: 99%

“…LINEs are prone to be spliced both in sense and antisense orientation . Since LINEs are much longer sequences compared to Alus, more regulators bind to them, and dozens of RBPs are highly enriched on LINEs . We found a number of RBPs show strong enrichment toward targeting of evolutionarily young LINEs, including MATR3, hnRNPM, and SUGP2.…”

Section: Many Rbps Bind To Intronic Rdes To Regulate Their Rna Procesmentioning

confidence: 99%

“…Firstly, exons arise about two‐times more frequently from evolutionarily old LINEs, and these exons show higher inclusion levels in more tissues, despite comparable strength of their splice site sequences. Secondly, MATR3 and PTBP1 were among the most enriched RBPs on intronic LINE sequences, and depletion of both proteins increased inclusion of cryptic exons derived from antisense L1s . Just as the hnRNPC‐repressed Alu‐exons, inclusion of such cryptic LINE‐exons tends to decrease the stability the mRNA isoform through NMD.…”

Section: Many Rbps Bind To Intronic Rdes To Regulate Their Rna Procesmentioning

confidence: 99%

“…Hence, LINEs have a high intrinsic propensity to exonize, but are generally efficiently repressed due to the function of RBPs acting in trans. Interestingly, LINEs are excluded in a wide window from established exons both in mouse and man, suggesting that they interfere with splicing of close‐by splice sites …”

Section: Many Rbps Bind To Intronic Rdes To Regulate Their Rna Procesmentioning

confidence: 99%

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Genomic Accumulation of Retrotransposons Was Facilitated by Repressive RNA‐Binding Proteins: A Hypothesis

Attig

Ule

2019

BioEssays

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Retrotransposon‐derived elements (RDEs) can disrupt gene expression, but are nevertheless widespread in metazoan genomes. This review presents a hypothesis that repressive RNA‐binding proteins (RBPs) facilitate the large‐scale accumulation of RDEs. Many RBPs bind RDEs in pre‐mRNAs to repress the effects of RDEs on RNA processing, or the formation of inverted repeat RNA structures. RDE‐binding RBPs often assemble on extended, multivalent binding sites across the RDE, which ensures repression of cryptic splice or polyA sites. RBPs thereby minimize the effects of RDEs on gene expression, which likely reduces the negative selection against RDEs. While mutations that change splice sites in RDEs act as an off‐on switch in exon formation, mutations that decrease the multivalency of RBP binding sites resemble a rheostat that enables a more gradual evolution of new RDE‐derived exons. RBPs might also repress aberrant processing of active retrotransposons, thus increasing the chance that full‐length copies are made. Taken together, in this review, it is proposed that RBPs facilitate the widespread accumulation of intronic RDEs by repressing RNA processing while chaperoning their potential to gradually evolve into new exons.

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Section: Many Rna‐binding Factors Bind Retrotransposons To Regulate Tmentioning

confidence: 99%

Section: Many Rbps Bind To Intronic Rdes To Regulate Their Rna Procesmentioning

confidence: 99%

Section: Many Rbps Bind To Intronic Rdes To Regulate Their Rna Procesmentioning

confidence: 99%

Section: Many Rbps Bind To Intronic Rdes To Regulate Their Rna Procesmentioning

confidence: 99%

Section: Many Rbps Bind To Intronic Rdes To Regulate Their Rna Procesmentioning

confidence: 99%

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Genomic Accumulation of Retrotransposons Was Facilitated by Repressive RNA‐Binding Proteins: A Hypothesis

Attig

Ule

2019

BioEssays

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Transposable elements as new players in neurodegenerative diseases

et al. 2021

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Neurodegenerative diseases (NDs), including the most prevalent Alzheimer’s disease and Parkinson disease, share common pathological features. Despite decades of gene‐centric approaches, the molecular mechanisms underlying these diseases remain widely elusive. In recent years, transposable elements (TEs), long considered ‘junk’ DNA, have gained growing interest as pathogenic players in NDs. Age is the major risk factor for most NDs, and several repressive mechanisms of TEs, such as heterochromatinization, fail with age. Indeed, heterochromatin relaxation leading to TE derepression has been reported in various models of neurodegeneration and NDs. There is also evidence that certain pathogenic proteins involved in NDs (e.g., tau, TDP‐43) may control the expression of TEs. The deleterious consequences of TE activation are not well known but they could include DNA damage and genomic instability, altered host gene expression, and/or neuroinflammation, which are common hallmarks of neurodegeneration and aging. TEs might thus represent an overlooked pathogenic culprit for both brain aging and neurodegeneration. Certain pathological effects of TEs might be prevented by inhibiting their activity, pointing to TEs as novel targets for neuroprotection.

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An update on post‐transcriptional regulation of retrotransposons

Warkocki

2022

FEBS Letters

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Retrotransposons, including LINE-1, Alu, SVA, and endogenous retroviruses, are one of the major constituents of human genomic repetitive sequences. Through the process of retrotransposition, some of them occasionally insert into new genomic locations by a copy-paste mechanism involving RNA intermediates. Irrespective of de novo genomic insertions, retrotransposon expression can lead to DNA double-strand breaks and stimulate cellular innate immunity through endogenous patterns. As a result, retrotransposons are tightly regulated by multi-layered regulatory processes to prevent the dangerous effects of their expression. In recent years, significant progress was made in revealing how retrotransposon biology intertwines with general posttranscriptional RNA metabolism. Here, I summarize current knowledge on the involvement of post-transcriptional factors in the biology of retrotransposons, focusing on LINE-1. I emphasize general RNA metabolisms such as methylation of adenine (m 6 A), RNA 3 0 -end polyadenylation and uridylation, RNA decay and translation regulation. I discuss the effects of retrotransposon RNP sequestration in cytoplasmic bodies and autophagy. Finally, I summarize how innate immunity restricts retrotransposons and how retrotransposons make use of cellular enzymes, including the DNA repair machinery, to complete their replication cycles.

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Heteromeric RNP Assembly at LINEs Controls Lineage-Specific RNA Processing

Cited by 139 publications

References 63 publications

Genomic Accumulation of Retrotransposons Was Facilitated by Repressive RNA‐Binding Proteins: A Hypothesis

Genomic Accumulation of Retrotransposons Was Facilitated by Repressive RNA‐Binding Proteins: A Hypothesis

Transposable elements as new players in neurodegenerative diseases

An update on post‐transcriptional regulation of retrotransposons

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