The Y3** ncRNA promotes the 3′ end processing of histone mRNAs

Köhn, Marcel; Ihling, Christian; Sinz, Andrea; Krohn, Knut; Hüttelmaier, Stefan

doi:10.1101/gad.266486.115

Cited by 30 publications

(41 citation statements)

References 35 publications

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“…Knockdown of the transcription elongation factors, NELF [40] and pTEF-B [41], as well as of Ars2 [42], a protein that directly interacts with FLASH and is important for cell cycle progression [43], results in small amounts of misprocessing of histone mRNA. Knockdown of a small ncRNA, Ro-RNA Y3*, has a similar effect, resulting in accumulation in read-through RNAs and alteration of HLB structure [44]. These results suggest that proper transcription elongation, together with factors in the HLB, also promotes coupling of processing and termination in mammalian cells.…”

Section: Cell-cycle Regulation Of Histone Mrnasmentioning

confidence: 99%

Birth and Death of Histone mRNAs

2017

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In metazoans, histone mRNAs are not polyadenylated but end in a conserved stem-loop. Stem-loop binding protein (SLBP) binds to the stem-loop and is required for all steps in histone mRNA metabolism. The genes for the five histone proteins are linked. A histone locus body (HLB) forms at each histone gene locus. It contains factors essential for transcription and processing of histone mRNAs, and couples transcription and processing. The active form of U7 snRNP contains the HLB component FLASH (FLICE-associated huge protein), the histone cleavage complex (HCC), and a subset of polyadenylation factors including the endonuclease CPSF73. Histone mRNAs are rapidly degraded when DNA replication is inhibited by a 3′ to 5′ pathway that requires extensive uridylation of mRNA decay intermediates.

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Section: Cell-cycle Regulation Of Histone Mrnasmentioning

confidence: 99%

Birth and Death of Histone mRNAs

2017

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“…Some polyadenylated core histone mRNAs are produced in small amounts in cultured cells as a result of knockdown of a number of factors (NELF (19), ARS2 (20), chromatin modifiers (21), P-TEFb (21), Y-RNAs (22) and SLBP (23)). These treatments likely result in a perturbation of canonical histone pre-mRNA processing after the stem-loop.…”

Section: Introductionmentioning

confidence: 99%

“…have shown that there is production of some polyadenylated and spliced histone H2B mRNAs when human fibroblasts are differentiated into adipocytes in vitro (24). In some of these studies, the relative proportion of polyadenylated mRNAs and properly processed mRNAs were determined and the amount of polyA+ RNA was very small (<5%) (19,22). In other studies, only increases in polyadenylated histone mRNAs over the very small amounts of polyadenylated histone mRNAs present in control cells was described (21).…”

Section: Introductionmentioning

confidence: 99%

A subset of replication-dependent histone mRNAs are expressed as polyadenylated RNAs in terminally differentiated tissues

et al. 2016

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Histone proteins are synthesized in large amounts during S-phase to package the newly replicated DNA, and are among the most stable proteins in the cell. The replication-dependent (RD)-histone mRNAs expressed during S-phase end in a conserved stem-loop rather than a polyA tail. In addition, there are replication-independent (RI)-histone genes that encode histone variants as polyadenylated mRNAs. Most variants have specific functions in chromatin, but H3.3 also serves as a replacement histone for damaged histones in long-lived terminally differentiated cells. There are no reported replacement histone genes for histones H2A, H2B or H4. We report that a subset of RD-histone genes are expressed in terminally differentiated tissues as polyadenylated mRNAs, likely serving as replacement histone genes in long-lived non-dividing cells. Expression of two genes, HIST2H2AA3 and HIST1H2BC, is conserved in mammals. They are expressed as polyadenylated mRNAs in fibroblasts differentiated in vitro, but not in serum starved fibroblasts, suggesting that their expression is part of the terminal differentiation program. There are two histone H4 genes and an H3 gene that encode mRNAs that are polyadenylated and expressed at 5- to 10-fold lower levels than the mRNAs from H2A and H2B genes, which may be replacement genes for the H3.1 and H4 proteins.

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“…112 Functional changes in the HLB during S phase As cells enter S-phase, there are at least two major events that together result in a massive increase in histone mRNA levels: initiation of histone gene transcription in response to activation of Cyclin E/Cdk2 in late G1 and activation of histone premRNA processing. Phosphorylation of NPAT by Cyclin E/ Cdk2 is essential for histone gene transcription, 26,27,34 and may also result in the recruitment of pre-mRNA processing factors to the HLB like Symplekin, 52 thereby activating histone premRNA processing.…”

Section: Knockdown Of Y3mentioning

confidence: 99%

Coordinating cell cycle-regulated histone gene expression through assembly and function of the Histone Locus Body

2017

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Metazoan replication-dependent (RD) histone genes encode the only known cellular mRNAs that are not polyadenylated. These mRNAs end instead in a conserved stem-loop, which is formed by an endonucleolytic cleavage of the pre-mRNA. The genes for all 5 histone proteins are clustered in all metazoans and coordinately regulated with high levels of expression during S phase. Production of histone mRNAs occurs in a nuclear body called the Histone Locus Body (HLB), a subdomain of the nucleus defined by a concentration of factors necessary for histone gene transcription and premRNA processing. These factors include the scaffolding protein NPAT, essential for histone gene transcription, and FLASH and U7 snRNP, both essential for histone pre-mRNA processing. Histone gene expression is activated by Cyclin E/Cdk2-mediated phosphorylation of NPAT at the G1-S transition. The concentration of factors within the HLB couples transcription with pre-mRNA processing, enhancing the efficiency of histone mRNA biosynthesis. KEYWORDSCell cycle; Drosophila; histone genes; mRNA processing; nuclear bodyProper utilization of genetic information in eukaryotes requires extensive three-dimensional organization of the genome and its associated proteins within the nucleus. The basic unit of genome organization is the nucleosome, an octamer of two molecules of each of the four core histone proteins (H2A, H2B, H3 and H4) that packages »147 base pairs of DNA. In mammalian cells, approximately 4£10 8 molcules of each core histone must be synthesized during S phase of the cell cycle to package the newly replicated DNA. Defects in this process result in genome instability that can contribute to human pathologies like cancer. Histone protein synthesis results from a large increase in production at the beginning of S phase of equal amounts of mRNAs encoding the four core nucleosomal histones, as well as histone H1. This highly coordinated gene expression event is performed by a set of transcription and pre-mRNA processing factors unique to replication dependent (RD) histone mRNA biosynthesis that assemble into a nuclear body tightly associated with RD histone genes called the histone locus body (HLB). HLB formation involves a combination of ordered and stochastic assembly steps, and cell cycle regulated changes in the HLB occur to activate histone gene expression during S phase. Here we describe the history of how the HLB was discovered followed by a discussion of HLB assembly mechanism and how the HLB functions in RD histone mRNA biosynthesis.

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The Y3** ncRNA promotes the 3′ end processing of histone mRNAs

Cited by 30 publications

References 35 publications

Birth and Death of Histone mRNAs

Birth and Death of Histone mRNAs

A subset of replication-dependent histone mRNAs are expressed as polyadenylated RNAs in terminally differentiated tissues

Coordinating cell cycle-regulated histone gene expression through assembly and function of the Histone Locus Body

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