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ALYREF is shared by polyadenylated and nonpolyadenylated mRNA processing and export pathways [iCLIP-seq]

ABSTRACT: we try to investigate the binding of ALYREF and NXF1 on histone mRNA when the cell treated with indicated siRNAs. ALYREF plays key roles in nuclear export of polyadenylated mRNAs and also modulates their 3' processing, but whether it is involved in regulating RNAs beyond polyadenylated mRNAs is unknown. The replication-dependent (RD) histone mRNAs are not polyadenylated, but end in a stem-loop (SL) structure. Here we demonstrate that ALYREF prevalently binds a region next to the SL on RD histone mRNAs. SL-binding protein (SLBP) directly interacts with ALYREF and ensures this binding. To examine how SLBP KD impact ALYREF distribution on the histone mRNA, we carried out ALYREF iCLIP in control and SLBP KD cells. To investigate the functional consequence for ALYREF binding on histone mRNAs, we isolated polyA+ and polyA- RNAs from control and ALYREF KD cells, and carried out RNA-seq separately.

ORGANISM(S): Homo sapiens

PROVIDER: GSE124735 | GEO | 2019/02/27

REPOSITORIES: GEO

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Anti-SLBP RIPchip data

2015-12-16 | GSE59915 | GEO

Anti-SLBP RIPchip data

Project description:The animal replication-dependent (RD) histone mRNAs are coordinately regulated with chromosome replication. They are the only known cellular mRNAs that are not polyadenylated. Instead, the mature transcripts end in at a conserved stem-loop (SL) structure. This SL structure interacts stably with the stem-loop binding protein (SLBP), which is involved in all aspects of RD-histone mRNA metabolism. We used several genomic methods, including RNA Binding Protein IP followed by microarray analysis (RIP-ChIP) to analyze the RNA binding landscape of SLBP. Reference based design on two color Agilent DNA microarrays. Experimental sample is labeled in Ch1 (Cy3), which are mRNA bound by the SLBP RNA-binding protein. The reference sample is labeled in Ch2 (Cy5) which are the polyribosomal mRNAs from the supernatant that were not bound by anti-SLBP. Controls included no antibody in the IP (which tends to have non-specific background binding to the beads) and pre-incubation of the SLBP with the antibodies antigenic peptide, which blocks antibody binding to the SLBP.

2015-12-16 | E-GEOD-59915 | biostudies-arrayexpress

ALYREF links 3'processing and nuclear export of histone mRNAs

Project description:To examine whether ALYREF can facilitate the 3'processing of RD histone mRNA,we isolated and sequenced the polyadenylated and nonpolyadenylated RNAs from control and ALYREF KD cells

2019-02-27 | GSE113422 | GEO

Biosynthesis of histone messenger RNA employs a specific 3' end endonuclease

Project description:During S-phase of the cell cycle production of the core histone proteins is precisely balanced with DNA replication. Metazoan mRNAs encoding replication dependent (RD) histones lack polyA tail normally formed by 3’ end cleavage and coupled polyadenylation of the pre-mRNA. Instead, they undergoes to endonucleolytic cleavage on the 3ʹ side of an RNA hairpin (stem loop) producing mRNA with a 3´-stem loop (SL), which is exported from the nucleus for use in translation. The same endonuclease that is involved in normal protein-coding pre-mRNA cleavage, i.e. cleavage and poyladenylation specificity factor 73 (CPSF73), is proposed to catalyse RD pre-histone mRNA cleavage. Additional factors specific to RD pre-histone mRNA processing, including stem loop binding protein (SLBP) and the U7 small nuclear ribonucleoprotein (U7snRNP) that binds to a histone downstream element (HDE) are thought to be involved in CPSF73 targeting to RD pre-histone mRNA. We report that a different histone specific endonuclease (HSE), which like CPSF73 is a metallo β lactamase (MBL) fold protein, is specific for RD pre-histone mRNA cleavage10,11. Crystallographic and biochemical studies reveal HSE has a di-zinc ion containing active site related to that of CPSF73, but which has distinct overall fold. Notably HSE depletion from cells leads to the production of unprocessed RD pre-histone mRNA due to inefficient 3ʹ end processing. The consequent depletion of core histone proteins correlates with a cell cycle defect due to a delay in entering/progressing through S-phase. HSE thus may represent a new type of S-phase specific cancer target.

2018-12-26 | GSE94686 | GEO

Dual RNA 3’ end processing of H2A.X messenger RNA maintains DNA damage repair throughout the cell cycle

Project description:Replication-dependent (RD) histone mRNA are the only non-polyadenylated protein coding transcripts in humans. However, a subset of RD histone genes also expresses polyadenylated mRNA upon terminal differentiation to maintain histone proteins. We now show that even in cycling cells, RD histone genes express some poly(A) mRNA. The H2AFX gene, encoding the DNA damage signalling histone variant H2A.X, expresses both an S-phase-specific SL mRNA ending in the typical stem-loop (SL) structure and substantial amounts of an extended poly(A) mRNA. We show, by the selective removal of either mRNA isoform, that the S-phase-specific H2A.X SL mRNA can generate sufficient histone for deposition onto DNA damage responsive (DDR) chromatin in some cell types. In contrast, when cells have evolved to make predominantly H2A.X poly(A) mRNA they then require de novo H2A.X for efficient DDR. This highlights the importance of differential H2AFX mRNA 3’ end processing for the maintenance of effective DDR

2020-11-23 | GSE144323 | GEO

Knock-outs of TUT7 and 3’hExo show that they cooperate in histone mRNA maintenance and degradation

Project description:Metazoan histone mRNAs are the only cellular eucaryotic mRNAs that are not polyadenylated, ending instead in a conserved stemloop. SLBP is bound to the 3’ end of histone mRNA and is required for translation of histone mRNA. Their expression is tightly cell-cycle regulated. A major regulatory step is rapid degradation of histone mRNA at the end of S-phase or when DNA synthesis is inhibited in S-phase. 3’hExo, a 3’ to 5’ exonuclease, binds to the SLBP/SL complex, and trims histone mRNA to 3 nts after the stemloop. Together with a terminal uridyl transferase, 3’hExo maintains the length of the histone mRNA during S-phase. 3’hExo is essential for initiating histone mRNA degradation on polyribosomes, initiating degradation into the 3’ side of the stemloop. There is extensive uridylation of degradation intermediates in the 3’ side of the stem when histone mRNA is degraded. Here we knocked out TUT7 and 3’hExo and we show that both modification of histone mRNA during S-phase and degradation of histone mRNA involve the interaction of 3’hExo, and a specific TUTase, TENT3B (TUT7, CHHC6). Knockout of 3’hExo prevents initiation of 3’ to 5’ degradation, stabilizing histone mRNA, while knockout of TUT7 prevents uridylation of the mRNA degradation intermediates slowing the rate of degradation. In synchronized 3’hExo KO cells, histone mRNA degradation is delayed but the histone mRNA is degraded prior to mitosis by a different pathway.

2022-08-01 | GSE203392 | GEO

Transcription elongation rate affects nascent histone pre-mRNA folding and 3’ end processing

Project description:We report that slow transcription by mutant RNA pol II caused accumulation of polyadenylated histone mRNAs that extend past the stem loop processing site. UV irradiation, which decelerates pol II elongation, also induced long poly(A)+ histone transcripts. Inhibition of 3’ processing by slow pol II correlates with failure to recruit SLBP to histone genes. Chemical probing of nascent RNA structure showed that the stem loop fails to fold in transcripts made by slow pol II, thereby explaining the absence of SLBP and failure to process 3’ ends. These results show that regulation of transcription speed can modulate pre-mRNA processing by changing nascent RNA structure, and suggest a mechanism by which alternative processing could be controlled

2018-02-23 | GSE109652 | GEO

eIF4E1b is a non-canonical eIF4E required for maternal mRNA dormancy

Project description:Maternal mRNAs are essential for protein synthesis during oogenesis and early embryogenesis. To adapt translation to specific needs during development, maternal mRNAs are translationally repressed by shortening the polyA tails. While mRNA deadenylation is associated with decapping and degradation in somatic cells, maternal mRNAs with short polyA tails are stable. Here we report an essential role for the germline-specific paralog of the mRNA cap-binding factor eIF4E, known as eIF4E1b, in the storage and repression of maternal mRNAs with short polyA tails. eIF4E1b binds to the mRNA cap and is targeted to ribonucleoprotein complexes through its direct interaction with eIF4ENIF1/4E-T. In early embryos, eIF4E1b binds to a specific set of translationally repressed mRNAs with short or no polyA tails, such as histone mRNAs, which are translated later on during embryogenesis. Consistent with an important role in maternal mRNA dormancy, mutation of eIF4E1b in zebrafish impairs female germline development. Understanding the mechanism and function of eIF4E1B provides new insights into fundamental post-transcriptional regulatory principles governing early vertebrate development.

2024-04-12 | PXD042434 | Pride

Global RNA-binding profile of the mRNA export adaptor ALYREF

Project description:The TREX complex (TREX) plays key roles in nuclear export of mRNAs. However, little is known about its transcriptome-wide binding targets. We used individual cross-linking and immunoprecipitation (iCLIP) to identify the binding sites of ALYREF, an mRNA export adaptor in TREX, in human cells. As expected, iCLIP reads are mainly mapped to exons of mRNAs. Globally, ALYREF binding shows two apparent enrichments on the mRNA, one is near the 5’ end and the other is very close to the 3’ end. In addition, numerous middle exons harbor ALYREF binding sites. CBP80 and PABPN1 mainly affect ALYREF binding at the 5’ and the 3’ region, respectively. Interestingly, we found that the 3’ processing factor CstF64 directly interacts with ALYREF and is required for the overall binding of ALYREF on the mRNA. Sequence analysis led to the identification of multiple

2017-05-19 | GSE99069 | GEO

Arsenic-induced polyadenylation of canonical histone H3.1 mRNA displaces histone variant H3.3 from critical gene regulatory regions

Project description:The replication-dependent canonical histone genes are the only genes found in multicellular organisms whose messenger RNA (mRNA) does not terminate with a poly(A) tail at the 3’ end. We previously demonstrated that arsenic exposure induces polyadenylation of canonical histone H3.1 mRNA in tissue culture system. We report that arsenic is capable of inducing high levels of H3.1 mRNA polyadenylation and marked loss of the Stem-loop binding protein (SLBP) in vivo, which is critical for canonical histone pre-mRNA processing. Ectopic expression of polyadenylated H3.1 mRNA enhances anchorage-independent cell growth and tumor formation in nude mice. Moreover, polyadenylation of H3.1 mRNA causes transcriptional deregulation, G2/M arrest, chromosome aneuploidy and aberration. Importantly, overexpression of H3.3 attenuates arsenic-induced cell transformation. Through ChIP-Seq and RNA-Seq, we try to decipher if polyadenylated H3.1 mRNA could result in depletion of histone variant H3.3 at critical gene regulatory regions. Our study uncovers polyadenylation of H3.1 and resulting displacement of variant H3.3 as a potential new mechanism for arsenic-induced carcinogenesis.

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