Uridylation by TUT4/7 Restricts Retrotransposition of Human LINE-1s

Warkocki, Zbigniew; Krawczyk, Paweł S.; Adamska, Dorota; Bijata, Krystian; García‐Pérez, José L.; Dziembowski, Andrzej

doi:10.1016/j.cell.2018.07.022

Cited by 80 publications

(110 citation statements)

References 76 publications

(116 reference statements)

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“…MOV10 is an ATP‐dependent RNA helicase that was first identified as a restriction factor of Moloney leukemia virus . MOV10 interacts with multiple enzymes that act as restriction factors of retrotransposons, including the adenosine deaminase ADAR1, the cytidine deaminase APOBEC3G, and the terminal uridylyltransferases TUT4/TUT7 . MOV10 inhibits retrotransposition of all human non‐LTR retrotransposons in cultured cells, most likely by promoting the activity of these enzymes, for example TUT4/TUT7.…”

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

confidence: 99%

“…In vitro, L1‐ORF1p inhibits the access of TUT4/7 and RNases to L1 RNA. MOV10 displaces L1 ORF1p and thus allows access of TUT4/7 to L1 RNA to promote its degradation and inhibit reverse transcription …”

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

confidence: 99%

“…[12] MOV10 interacts with multiple enzymes that act as restriction factors of retrotransposons, including the adenosine deaminase ADAR1, the cytidine deaminase APOBEC3G, and the terminal uridylyltransferases TUT4/TUT7. [13][14][15][16][17] MOV10 inhibits retrotransposition of all human non-LTR retrotransposons in cultured cells, [18,19] most likely by promoting the activity of these enzymes, for example TUT4/TUT7. When a poly(A) tail is shortened and not protected by poly(A)-binding proteins, TUT4 and TUT7 act as terminal uridylyltransferases to promote mRNA decay.…”

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

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 Rna‐binding Factors Bind Retrotransposons To Regulate Tmentioning

confidence: 99%

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

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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“…Only HNRNPU was observed to be a significant hit in two different patient tumors. Notably, HNRNPU, DHX9, MATR3, HNRNPC, and other RNA binding proteins have been reported to accumulate on L1 and retro-element-derived RNAs; in one hypothesis, insulating these sequences from nuclear RNA processing pathways that might otherwise be deleterious to the retro-element and host genes harboring these sequences [41,42]. The data can otherwise be summarized as follows: 291 proteins passed at least one t-test (tumor vs. control IP: p-adjusted value of ≤ 0.05 and ≥ two-fold enrichment in tumor IP), 37 passed two, and 22 passed three or more; 21 candidate non-consensus ORF1p loci were detected and of these 12 were observed in both tumor A and tumor B.…”

Section: Characterizing L1 Immunoprecipitates From Crcsmentioning

confidence: 99%

LINE-1 ORF2p Expression is Nearly Imperceptible in Human Cancers

Ardeljan

Wang

Oghbaie

et al. 2019

Preprint

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Background: Long interspersed element-1 (LINE-1, L1) is the major driver of mobile DNA activity in modern humans. When expressed, LINE-1 loci produce bicistronic transcripts encoding two proteins essential for retrotransposition, ORF1p and ORF2p. Many types of human cancers are characterized by L1 promoter hypomethylation, L1 transcription, L1 ORF1p protein expression, and somatic L1 retrotransposition. ORF2p encodes the endonuclease and reverse transcriptase activities required for L1 retrotransposition. Its expression is poorly characterized in human tissues and cell lines. Results:We report mass spectrometry based tumor proteome profiling studies wherein ORF2p eludes detection. To test whether ORF2p could be detected with specific reagents, we developed and validated five rabbit monoclonal antibodies with immunoreactivity for specific epitopes on the protein. These reagents readily detect ectopic ORF2p expressed from bicistronic L1 constructs. However, endogenous ORF2p is not detected in human tumor samples or cell lines by western blot, immunoprecipitation, or immunohistochemistry despite high levels of ORF1p expression. Moreover, we report endogenous ORF1p-associated interactomes, affinity isolated from colorectal cancers, wherein we similarly fail to detect ORF2p. These samples include primary tumors harboring hundreds of somatically-acquired L1 insertions. The new data are available via ProteomeXchange with identifier PXD013743. Conclusions:Although somatic retrotransposition provides unequivocal genetic evidence for the expression of ORF2p in human cancers, we are unable to directly measure its presence using several standard methods. Experimental systems have previously indicated an unequal stoichiometry between ORF1p and ORF2p, but in vivo, the expression of these two proteins may be more strikingly uncoupled. These findings are consistent with observations that ORF2p is not tolerable for cell growth. References

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“…Additionally, the recent finding that LINE-1 elements are modified by TUT4/TUT7 uridylyltransferases to impede mobilization (Warkocki et al 2018) suggests that these modifications may also be protective against proliferation of transposable elements.…”

Section: Discussionmentioning

confidence: 99%

A non-Dicer RNase III and four other novel factors required for RNAi-mediated transposon suppression in the human pathogenic yeastC. neoformans

Burke

Longhurst

Natarajan

et al. 2019

Preprint

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The human pathogenic yeast Cryptococcus neoformans silences transposable elements using endo-siRNAs and an Argonaute, Ago1. Endo-siRNAs production requires the RNA-dependent RNA polymerase, Rdp1, and two partially redundant Dicer enzymes, Dcr1 and Dcr2, but is independent of histone H3 lysine 9 methylation. We describe here an insertional mutagenesis screen for factors required to suppress the mobilization of the C. neoformans HARBINGER family DNA transposon HAR1. Validation experiments uncovered five novel genes (RDE1-5) required for HAR1 suppression and global production of suppressive endo-siRNAs. Loss of the RDE genes does not impact transcript levels, suggesting the endo-siRNAs do not act by impacting target transcript synthesis or turnover. RDE3 encodes a non-Dicer RNase III related to S. cerevisiae Rnt1, RDE4 encodes a predicted terminal nucleotidyltransferase, while RDE5 has no strongly predicted encoded domains. Affinity purification-mass spectrometry studies reveal that Rde3 and Rde5 are physically associated. RDE1 encodes a G-patch protein homologous to the S. cerevisiae Sqs1/Pfa1, a nucleolar protein that directly activates the essential helicase Prp43 during rRNA biogenesis. Rde1 copurifies Rde2, another novel protein obtained in the screen, as well as Ago1, a homolog of Prp43, and numerous predicted nucleolar proteins. We also describe the isolation of conditional alleles of PRP43, which are defective in RNAi. This work reveals unanticipated requirements for a non-Dicer RNase III and presumptive nucleolar factors for endo-siRNA biogenesis and transposon mobilization suppression in C. neoformans.

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Uridylation by TUT4/7 Restricts Retrotransposition of Human LINE-1s

Cited by 80 publications

References 76 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

LINE-1 ORF2p Expression is Nearly Imperceptible in Human Cancers

A non-Dicer RNase III and four other novel factors required for RNAi-mediated transposon suppression in the human pathogenic yeastC. neoformans

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