Yra1 Is Required for S Phase Entry and Affects Dia2 Binding to Replication Origins

Swaminathan, Swarna; Kile, Andrew C.; Macdonald, Elizabeth; Koepp, Deanna M.

doi:10.1128/mcb.02052-06

Cited by 20 publications

(27 citation statements)

References 46 publications

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“…These results support that Aly is required for cell cycle progression. This finding corroborates with the recent report that Yra1, a yeast homolog of Aly, is required for S phase entry and affects Dia2 binding to replication origins (24). Thus, Aly mediates cell cycle and has a role in DNA replication.…”

Section: Discussionsupporting

confidence: 82%

“…Yra1, a yeast homolog of Aly, is required for S phase entry and plays a role in DNA replication in yeast (24). To explore whether Aly mediates cell proliferation, we knocked it down with its specific siRNA.…”

Section: Depletion Of Aly Suppresses Cell Proliferation and Reduces Mrnamentioning

confidence: 99%

“…Recently, it has been shown that Yra1 is required for S phase entry and affects Dia2 binding to replication origins. Thus, it has a role in DNA replication distinct from its role in mRNA export (24). Although Aly directly binds UAP56 and couples it to spliced mRNA, REF/Aly is dispensable for mRNA export in Drosophila (25) and Caenorhabditis elegans (26).…”

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confidence: 99%

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Akt phosphorylation and nuclear phosphoinositide association mediate mRNA export and cell proliferation activities by ALY

Okada

Jang

2008

Proc. Natl. Acad. Sci. U.S.A.

102

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Nuclear PI3K and its downstream effectors play essential roles in a variety of cellular activities including cell proliferation, survival, differentiation, and pre-mRNA splicing. Aly is a nuclear speckle protein implicated in mRNA export. Here we show that Aly is a physiological target of nuclear PI3K signaling, which regulates its subnuclear residency, cell proliferation, and mRNA export activities through nuclear Akt phosphorylation and phosphoinositide association. Nuclear Akt phosphorylates Aly on threonine-219, which is required for its interaction with Akt. Aly binds phosphoinositides, and this action is regulated by Akt-mediated phosphorylation. Phosphoinositide binding but not Akt phosphorylation dictates Aly's nuclear speckle residency. Depletion of Aly results in cell growth suppression and mRNA export reduction. Inhibition of Aly phosphorylation substantially decreases cell proliferation and mRNA export. Furthermore, disruption of phosphoinositide association with Aly also significantly reduces these activities. Thus, nuclear PI3K signaling mediates both cell proliferation and mRNA export functions of Aly.nuclear PI 3-kinase ͉ nuclear speckle ͉ nuclear Akt ͉ T219 phosphorylation P I3K and Akt predominantly locate in the cytoplasm, but they also occur in the nucleus or translocate there upon stimulation. Most of phosphoinositol lipid metabolic enzymes and PI3K signaling machinery occur in the nucleus. For example, PI-PLC (1, 2), phosphatidylinositol phosphate kinases (3, 4), PDK1 (5), PTEN (6 -8), and Akt (9, 10). Nuclear phosphoinositides play critical roles in cell growth and differentiation (11). In addition to nuclear membrane, phosphoinositides also associate with the nuclear speckles, a peculiar nuclear subcompartment enriched in small ribonucleoprotein (RNP) particles and various splicing factors (12), where many elements of nuclear phosphoinositide metabolism, including PI(4,5)P 2 , are concentrated (4,13,14). Nuclear phosphoinositides may be implicated in pre-mRNA splicing and chromatin structure (11). It has been shown before that nuclear PI(4,5)P 2 assembles in a mitotically regulated particle involved in pre-mRNA splicing (14). Elements of the transcriptional and pre-mRNA processing machinery interact with this pool of nuclear PI(4,5)P 2 , and PI(4,5)P 2 immunoprecipitates contain intermediates and products of the splicing reaction. Alternative splicing of pre-mRNAs can be regulated by extracellular signals such as growth factors, cytokines, hormones, and stress stimuli (15). For instance, insulin-activated PI3K signaling has been shown to implicate in mammary epithelial-mesenchymal interaction, which regulates fibronectin alternative splicing (16).Splicing of pre-mRNA and export of mRNA are normally coupled (17-19). Pre-mRNA splicing has been proposed to stimulate mRNA export (17,20). Based on genetic and biochemical evidence, Reed et al. (21) proposed a model for mRNA export: nascent pre-mRNA is first packaged into heterogeneous nuclear RNP (hnRNP) particles. During spliceosome assembly,...

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Section: Discussionsupporting

confidence: 82%

Section: Depletion Of Aly Suppresses Cell Proliferation and Reduces Mrnamentioning

confidence: 99%

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Akt phosphorylation and nuclear phosphoinositide association mediate mRNA export and cell proliferation activities by ALY

Okada

Jang

2008

Proc. Natl. Acad. Sci. U.S.A.

102

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“…At high concentrations (~200 mM), HU induces S-phase arrest of S. cerevisiae [43], thus it is possible that an increase in repair during a prolonged S-phase is responsible for the effect of HU. To determine whether the HU-mediated inhibition of mutation (which occurs at concentrations as low as 10 mM), results from a prolonged S-phase, the UV-induced mutation frequency with or without HU was determined in an S-phase arrest deficient rad53Δ mutant.…”

Section: Hydroxyurea Inhibits Induced Mutagenesismentioning

confidence: 99%

“…A similar reduction in UV-induced mutation frequency was observed with lys2ΔBgl reversion ( Figure 5A), implying that HU inhibits the formation of both point mutations and frameshift mutations. In addition, HU also potently inhibits EMS-induced mutation ( Figure S6), and its inhibition of UV-mutation is independent of RAD30, POL32, and REV3 (Table 3), further suggesting that HU specifically inhibits the same pathway that is mediated by Rnr4.At high concentrations (~200 mM), HU induces S-phase arrest of S. cerevisiae [43], thus it is possible that an increase in repair during a prolonged S-phase is responsible for the effect of HU. To determine whether the HU-mediated inhibition of mutation (which occurs at concentrations as low as 10 mM), results from a prolonged S-phase, the UV-induced mutation frequency with or without HU was determined in an S-phase arrest deficient rad53Δ mutant.…”

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confidence: 96%

Identification of pathways controlling DNA damage induced mutation in Saccharomyces cerevisiae

Lis¹,

O'Neill²,

Gil-Lamaignere³

et al. 2008

DNA Repair

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Mutation in response to most types of DNA damage is thought to be mediated by the error-prone sub-branch of post-replication repair and the associated translesion synthesis polymerases. To further understand the mutagenic response to DNA damage, we screened a collection of 4848 haploid gene deletion strains of Saccharomyces cerevisiae for decreased damage-induced mutation of the CAN1 gene. Through extensive quantitative validation of the strains identified by the screen, we identified ten genes, which included error-prone post-replication repair genes known to be involved in induced mutation, as well as two additional genes, FYV6 and RNR4. We demonstrate that FYV6 and RNR4 are epistatic with respect to induced mutation, and that they function, at least partially, independently of post-replication repair. This pathway of induced mutation appears to be mediated by an increase in dNTP levels that facilitates lesion bypass by the replicative polymerase Polδ, and it is as important as error-prone post-replication repair in the case of UV-and MMS-induced mutation, but solely responsible for EMS-induced mutation. We show that Rnr4/Polδ-induced mutation is efficiently inhibited by hydroxyurea, a small molecule inhibitor of ribonucleotide reductase, suggesting that if similar pathways exist in human cells, intervention in some forms of mutation may be possible. Keywordsyeast; post-replication repair; induced mutagenesis 1.IntroductionThe stability of the genome is critical for life, but mutation occurs as a result of both exogenous and endogeneous mutagens [1]. Mutations contribute to ageing [2], oncogenesis, tumor progression [3][4][5], and resistance to chemotherapy [6][7][8]. Ironically, because many chemotherapeutic drugs are mutagens, they may themselves play a role in inducing the mutations that give rise to resistance and therapy failure [9][10][11].For many years, it was assumed that mutagens induced DNA damage, and the damaged DNA caused the replicative polymerases to make errors during DNA replication. However, it is now understood that most types of DNA damage inhibit DNA replication, and that the cellular response to this inhibition is critical for the induction of mutation. The cellular response to replication blocks in the yeast Saccharomyces cerevisiae has been intensively studied and is 1Corresponding author Floyd E. Romesberg, Department of Chemistry, The Scripps Research Institute, CB262R, 10550 N. Torrey Pines Rd, La Jolla, CA, 92037, Phone: (858) Fax: (858) 784-7472, E-mail: floyd@scripps.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Pub...

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Regulation of mRNP dynamics along the export pathway

Iglesias

Stutz

2008

FEBS Letters

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The transcription of mRNA is tightly coupled to the concomitant recruitment of mRNA processing and export factors, resulting in the formation of mature and export competent mRNP complexes. This interconnection in gene expression implies extensive spatio-temporal control of mRNP dynamics to prevent mRNA export factors bound to pre-mRNA from functioning at the incorrect time and exporting nascent or incompletely processed pre-mRNAs. Recent discoveries provide molecular understanding of how a broad range of post-translational modifications together with RNA-dependent ATPases coordinate proteins acting at different steps and regulate mRNP assembly and export.

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Yra1 Is Required for S Phase Entry and Affects Dia2 Binding to Replication Origins

Cited by 20 publications

References 46 publications

Akt phosphorylation and nuclear phosphoinositide association mediate mRNA export and cell proliferation activities by ALY

Akt phosphorylation and nuclear phosphoinositide association mediate mRNA export and cell proliferation activities by ALY

Identification of pathways controlling DNA damage induced mutation in Saccharomyces cerevisiae

Regulation of mRNP dynamics along the export pathway

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