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Uridylation by TUT4 and TUT7 marks mRNA for degradation [RNA-Seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE59626 | GEO | 2014/12/04

SECONDARY ACCESSION(S): PRJNA255776

REPOSITORIES: GEO

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Uridylation by TUT4 and TUT7 marks mRNA for degradation [RNA-Seq]

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. HeLa cells were knocked down of control or TUT4/7, then total RNAs were prepared for RNA-seq on 0, 1, 2, 4h after actinomycin D treatment. The whole processes of experiments were repeated two times.

2014-12-04 | E-GEOD-59626 | biostudies-arrayexpress

Uridylation by TUT4 and TUT7 marks mRNA for degradation [TAIL-Seq]

2014-12-04 | GSE59627 | GEO

Uridylation by TUT4 and TUT7 marks mRNA for degradation [TAIL-Seq]

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. Thirteen separate sets of TAIL-seq experiments were performed. Each set includes a negative control for transfection, immunoprecipitation, or knockout cell generation. Experimental samples were treated with various conditions including siRNA transfection, transdominant negative protein expression, TALEN-based gene knockout, or immunoprecipitation. The 'README-TAIL-seq.txt' include detailed information about structure of seq entries in FASTQ files and of processed data for 3' end modifications.

2014-12-04 | E-GEOD-59627 | biostudies-arrayexpress

Role of TUT4 and TUT7 on the regulation of MHV poly(A) tail length and 3' end additions [17-CL1_Mutants]

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.

2023-03-23 | GSE200413 | GEO

Maternal mRNA degradation by TUT4 and TUT7 in the zebrafish maternal-to-zygotic transition

Project description:During the maternal-to-zygotic transition (MZT), maternal RNAs are actively degraded and replaced by newly-synthesized zygotic transcripts in a highly coordinated manner. However, it remains largely unknown how maternal mRNA decay is triggered in early vertebrate embryos. Here, through genome-wide profiling of RNA abundance and 3′ modification, we show that uridylation is induced at the onset of maternal mRNA clearance. The temporal control of uridylation is conserved in vertebrates. When the homologs of terminal uridylyltransferases TUT4 and TUT7 (TUT4/7) are depleted in zebrafish and Xenopus, maternal mRNA clearance is significantly delayed, leading to developmental defects during gastrulation. Short-tailed mRNAs are selectively uridylated by TUT4/7, with the highly uridylated transcripts degraded faster during the MZT than those with unmodified poly(A) tails. Our study demonstrates that uridylation plays a crucial role in timely mRNA degradation, thereby allowing the progression of early development.

2018-04-13 | GSE111152 | GEO

Sensing the end: how TUT7 controls the fate of precursor microRNAs by uridylation

Project description:Terminal uridylyl transferases (TUTs) function as integral regulators of microRNA (miRNA) biogenesis by modifying the end structure of precursor miRNA (pre-miRNA). Using biochemistry and deep sequencing techniques, we here investigate the mechanism how human TUT7 recognizes and uridylates pre-miRNAs. We show that the overhang of a pre-miRNA is the key structural element that TUT7 and its paralogues, TUT4 and TUT2, recognize. For group II pre-miRNAs which have a 1 nt 3’ overhang, TUT7 restores the canonical end structure (2 nt 3’ overhang) by mono-uridylation, and thereby promotes miRNA biogenesis. Interestingly, once the 3’ end is receded into the stem (3’ trimmed pre-miRNAs such as Ago-cleaved-pre-miRNA), TUT7 effectively generates an oligo-U tail that consequently leads to degradation. Our single-molecule study further suggests that a distributive mode is employed for both pathways, but the overhang length determines the frequency of TUT7-RNA interaction. Our results explain how TUT7 and TUT4 differentiate pre-miRNA species and reveal a role for TUT7 and TUT4 in the oligo-uridylation and removal of defective pre-miRNAs.

2015-04-30 | GSE64482 | GEO

Sensing the end: how TUT7 controls the fate of precursor microRNAs by uridylation

2015-04-30 | E-GEOD-64482 | biostudies-arrayexpress

TUT7 Catalyzes the Uridylation of the 3’ End for Rapid Degradation of Histone mRNA

Project description:Using high-throughput sequencing of histone mRNAs and degradation intermediates, we find that knockdown of TUT7 reduces both the uridylation at the 3’ end as well as uridylation pattern at the 3’ end, and only had a small effect on the uridylation in the stemloop uridylation of the major during histone mRNA degradation. Knockdown of 3’ hEXO also altered the uridylation of histone mRNAs, revealing a dynamic equilibrium between 3’ hEXO digestion and TUT7 uridylation, suggesting that TUT7 and 3’ hExo function together in trimming and uridylating histone mRNAs.

2016-08-29 | GSE85361 | GEO

Sequence-specific mono-uridylation of mature miRNAs by Zcchc6 and Zcchc11

Project description:Recent small RNA sequencing data has uncovered extensive modification of the 3’ end of mature microRNAs (miRNAs). This non-templated nucleotide addition can impact miRNA gene regulatory networks through the control of miRNA stability or by interfering with the repression of target mRNAs. The miRNA modifying enzymes responsible for this regulation remain largely uncharacterized. Here we describe the ability for two related terminal uridyl transferases (TUTases), Zcchc6 (TUT7) and Zcchc11 (TUT4), to 3’ mono-uridylate a specific subset of miRNAs involved in cell differentiation and Hox gene control. Zcchc6/11 selectively uridylate these miRNAs in vitro, and we biochemically define a bipartite sequence motif that is necessary and sufficient to confer Zcchc6/11 catalyzed uridylation. Depletion of these TUTases in cultured cells causes the selective loss of 3’ mono-uridylation of many of the same miRNAs. Interestingly, upon TUTase dependent loss of uridylation we observe a concomitant increase in non-templated 3’ mono-adenylation. Our results uncover the molecular basis for sequence specific miRNA mono-uridylation by Zcchc6/11, highlight the precise control of different 3’ miRNA modifications in cells, and have implications for miRNA regulation during development. small RNA profiles in TUTases knock-down and control HeLa cells were generated by Illumina deep sequencing

2013-12-01 | E-GEOD-52575 | biostudies-arrayexpress

Small RNA profiling of TUT4 and TUT7-deficient mouse pachytene-diplotene cells.

Project description:To study the impact of TUT4 and TUT7 on miRNA and piRNA biology, Tut4 and Tut7 were conditionally deleted in differentiating spermatogonia. Total RNA samples from TUT4 and TUT7-deficient pachytene-diplotene cells were used to generate small RNAs libraries.

2019-01-14 | E-MTAB-7065 | biostudies-arrayexpress

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