Uridilation by TUT4/7 restricts retrotransposition of human Line-1s
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ABSTRACT:
PROVIDER: PRJNA415171 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6195820_1.fastq.gz | Fastqsanger.gz | |||
| SRR6195820_2.fastq.gz | Fastqsanger.gz | |||
| SRR6195830_1.fastq.gz | Fastqsanger.gz | |||
| SRR6195830_2.fastq.gz | Fastqsanger.gz | |||
| SRR6195840_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: the goal of this study was to test whether the amounts of genome-encoded Line-1s are influenced by TUTases and Mov10 Methods: RNA-Seq data were obtained for PA-1 or Hek293 Flp-IN T-Rex cells in which wild-type or mutant TUTases or Mov10 were overexpressed or the proteins were depleted by RNA interference Results: Minor changes (less than 0.4-fold) were observed in the amounts of mRNAs of Homo sapiens-specific Line-1 families in Hek293 Flp-IN T-Rex and PA-1 either overexpressing or depleted of TUTases and Mov10
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Project description:LINE-1 retrotransposition is tightly restricted by layers of regulatory control, with epigenetic pathways being the best characterized. Looking at post-transcriptional regulation, we now show that LINE-1 mRNA 3' ends are pervasively uridylated in various human cellular models and in mouse testes. TUT4 and TUT7 uridyltransferases catalyze the modification and function in cooperation with the helicase/RNPase MOV10 to counteract the RNA chaperone activity of the L1-ORF1p retrotransposon protein. Uridylation potently restricts LINE-1 retrotransposition by a multilayer mechanism depending on differential subcellular localization of the uridyltransferases. We propose that uridine residues added by TUT7 in the cytoplasm inhibit initiation of reverse transcription of LINE-1 mRNAs once they are reimported to the nucleus, whereas uridylation by TUT4, which is enriched in cytoplasmic foci, destabilizes mRNAs. These results provide a model for the post-transcriptional restriction of LINE-1, revealing a key physiological role for TUT4/7-mediated uridylation in maintaining genome stability.
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Project description:Adenosine deaminases acting on RNA (ADARs) are involved in RNA editing that converts adenosines to inosines in double-stranded RNAs. ADAR1 was demonstrated to be functional on different viruses exerting either antiviral or proviral effects. Concerning HIV-1, several studies showed that ADAR1 favors viral replication. The aim of this study was to investigate the composition of the ADAR1 ribonucleoprotein complex during HIV-1 expression. By using a dual-tag affinity purification procedure in cells expressing HIV-1 followed by mass spectrometry analysis, we identified 14 non-ribosomal ADAR1-interacting proteins, most of which are novel. A significant fraction of these proteins were previously demonstrated to be associated to the Long INterspersed Element 1 (LINE1 or L1) ribonucleoparticles and to regulate the life cycle of L1 retrotransposons that continuously re-enter host-genome.Hence, we investigated the function of ADAR1 in the regulation of L1 activity.By using different cell-culture based retrotransposition assays in HeLa cells, we demonstrated a novel function of ADAR1 as suppressor of L1 retrotransposition. Apparently, this inhibitory mechanism does not occur through ADAR1 editing activity. Furthermore, we showed that ADAR1 binds the basal L1 RNP complex. Overall, these data support the role of ADAR1 as regulator of L1 life cycle.
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Project description:TUT4 and TUT7 are terminal uridyl transferases that adds uridine bases to the 3′ end of RNAs such as miRNAs and mRNAs. The overall aim of this experiment was to identify differentially regulated mRNAs and miRNAs in catalytic knockouts of TUT4/7 relative to the wildtype. Catalytic mutants of TUT4/7 was generated in the prostate cancer cell line DU145 and the ovarian cancer cell line IGROV1. As the miRNA regulation by TUT4/7 depends on the oncoprotein LIN28A, LIN28A was lentivirally integrated in the LIN28A- DU145-derived lines and control. IGROV1 endogenously expresses LIN28A. We report that excluding the let-7 family, miRNAs do not depend on LIN28A for TUT4/7-mediated regulation. As the entire miRNA is captured in a read, we provide the isomiR landscape in the presence and absence of TUT4/7. Loss of uridylated isomiRs results in a simultaneous gain in adenylated isomiRs. Finally, we report cell line specific miRNA-mRNA regulation.
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Project description:Using single-cell genomics, we demonstrated that endogenous LINE-1s are mobilized in human pre-implantation embryos
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Project description:RNA ligation precedes U6 snRNA/LINE-1 retrotransposition
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Project description:LINE-1 (L1) insertions comprise as much as 17% of the human genome sequence, and similar proportions have been recorded for other mammalian species. Given the established role of L1 retrotransposons in shaping mammalian genomes, it becomes an important task to track and annotate the sources of this activity: full length elements, able to encode the cis and trans acting components of the retrotransposition machinery. The L1Base database (http://l1base.charite.de) contains annotated full-length sequences of LINE-1 transposons including putatively active L1s. For the new version of L1Base, a LINE-1 annotation tool, L1Xplorer, has been used to mine potentially active L1 retrotransposons from the reference genome sequences of 17 mammals. The current release of the human genome, GRCh38, contains 146 putatively active L1 elements or full length intact L1 elements (FLIs). The newest versions of the mouse, GRCm38 and the rat, Rnor_6.0, genomes contain 2811 and 492 FLIs, respectively. Most likely reflecting the current level of completeness of the genome project, the latest reference sequence of the common chimpanzee genome, PT 2.19, only contains 19 FLIs. Of note, the current assemblies of the dog, CF 3.1 and the sheep, OA 3.1, genomes contain 264 and 598 FLIs, respectively. Further developments in the new version of L1Base include an updated website with implementation of modern web server technologies. including a more responsive design for an improved user experience, as well as the addition of data sharing capabilities for L1Xplorer annotation.
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Project description:Uridylation occurs pervasively on mRNAs in mammals, yet its mechanism and significance remain unknown. Here we identify TUT4 and TUT7 (also known as ZCCHC11 and ZCCHC6, respectively) as the enzymes that uridylate mRNAs. Uridylation readily occurs on deadenylated mRNAs that are not associated with poly(A) binding protein (PABPC1) in cells. Consistently, purified TUT4 and TUT7 (TUT4/7) selectively uridylate RNAs with short A tails (< ~25 nt) while PABPC1 antagonizes uridylation of polyadenylated mRNAs in vitro. In cells depleted of TUT4/7, the vast majority of mRNAs lose the U tails, and their half-lives are extended. Suppression of mRNA decay factors leads to the accumulation of uridylated mRNAs. In line with this, microRNA induces uridylation of its targets, and TUT4/7 is required for enhanced decay of microRNA targets. Our study explains the mechanism underlying selective uridylation of deadenylated mRNAs, and demonstrates a fundamental role of the U tail as a molecular mark for global mRNA decay.
2014-12-04 | GSE59627 | GEO
Project description:Uridylation occurs pervasively on mRNAs in mammals, yet its mechanism and significance remain unknown. Here we identify TUT4 and TUT7 (also known as ZCCHC11 and ZCCHC6, respectively) as the enzymes that uridylate mRNAs. Uridylation readily occurs on deadenylated mRNAs that are not associated with poly(A) binding protein (PABPC1) in cells. Consistently, purified TUT4 and TUT7 (TUT4/7) selectively uridylate RNAs with short A tails (< ~25 nt) while PABPC1 antagonizes uridylation of polyadenylated mRNAs in vitro. In cells depleted of TUT4/7, the vast majority of mRNAs lose the U tails, and their half-lives are extended. Suppression of mRNA decay factors leads to the accumulation of uridylated mRNAs. In line with this, microRNA induces uridylation of its targets, and TUT4/7 is required for enhanced decay of microRNA targets. Our study explains the mechanism underlying selective uridylation of deadenylated mRNAs, and demonstrates a fundamental role of the U tail as a molecular mark for global mRNA decay.
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Project description:Terminal uridylation of mRNAs poly(A) tails by Terminal Uridylyl Transferases (TUTs) promote transcript decay. Here, we investigate the role of two functionally redundant mammalian TUTs, TUT4 and TUT7 (TUT4/7), in mouse hepatitis virus (MHV) RNA processing. We generated a TUT4/7 knock-down 17-CL1 cell line using lentivirus encoding shRNAs against Tut4 and Tut7 transcripts (shTUT4/7) and a control 17-CL1 cell line (shCTL) with a non-targeting shRNA. We then infected the shCTL and shTUT4/7 cells with MHV and isolated RNA at 24- and 48-hours post-infection (hpi). We found that viral RNA poly(A) tails of about 20 and 40 nucleotides are highly uridylated and that the uridylation of the 20 nucleotide long tails is dependent on TUT4/7. Depletion of TUT4/7 also resulted in an accumulation of the viral RNA.
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