Trm9-Catalyzed tRNA Modifications Link Translation to the DNA Damage Response

Begley, Ulrike; Dyavaiah, Madhu; Patil, Ashish; Rooney, John P.; DiRenzo, Dan; Young, Christine M.; Conklin, Douglas S.; Zitomer, R S; Begley, Thomas J.

doi:10.1016/j.molcel.2007.09.021

Cited by 289 publications

(431 citation statements)

References 36 publications

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“…The specificity of the observed phenotypes both in fission yeast and in worm is in favor of the second possibility and is reminiscent of the specific phenotype (cell cycle arrest) resulting from the absence of wobble inosine in fission yeast (40). This is also supported by a very recent study showing that deletion of the Trm9 tRNA ARG and tRNA GLU methyltransferase affects the translation of transcripts overrepresented with specific arginine and glutamate codons while the translation of average transcripts that contain a normal codon usage pattern is unaffected (41).…”

Section: Discussionmentioning

confidence: 70%

The conserved Wobble uridine tRNA thiolase Ctu1–Ctu2 is required to maintain genome integrity

Dewez

Bauer

Dieu³

et al. 2008

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

131

155

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Modified nucleosides close to the anticodon are important for the proper decoding of mRNA by the ribosome. Particularly, the uridine at the first anticodon position (U34) of glutamate, lysine, and glutamine tRNAs is universally thiolated (S 2 U34), which is proposed to be crucial for both restriction of wobble in the corresponding split codon box and efficient codon-anticodon interaction. Here we show that the highly conserved complex Ctu1-Ctu2 (cytosolic thiouridylase) is responsible for the 2-thiolation of cytosolic tRNAs in the nematode and fission yeast. In both species, inactivation of the complex leads to loss of thiolation on tRNAs and to a thermosensitive decrease of viability associated with marked ploidy abnormalities and aberrant development. Increased level of the corresponding tRNAs suppresses the fission yeast defects, and our data suggest that these defects could result from both misreading and frame shifting during translation. Thus, a translation defect due to unmodified tRNAs results in severe genome instability.thiolation ͉ yeast

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Section: Discussionmentioning

confidence: 70%

The conserved Wobble uridine tRNA thiolase Ctu1–Ctu2 is required to maintain genome integrity

Dewez

Bauer

Dieu³

et al. 2008

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

131

155

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“…Similar to other modifications, it is not clear whether transcription efficiency or fidelity or both are affected when the codon AAA has to be decoded by unmodified tRNA UUU Lys ; although Begley et al (35) described that S. cerevisiae Trm9-mediated tRNA modifications participate in the DNA damage response by enhancing translation elongation of general and specific stress proteins, they also reported later that those tRNA modifications lead to translation infidelity of specific transcripts, misfolding of the resulting proteins, and activation of the unfolded protein response pathway (36). Similarly, it has recently been suggested that Elongator mutants in budding yeast display basal proteostasis defects due to inefficient or incorrect translation, and this basal phenotype may be exacerbated in the presence of stress conditions (37).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide Screening of Regulators of Catalase Expression

Garcia¹,

Dedo²,

Ayté

et al. 2016

Journal of Biological Chemistry

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In response to environmental cues, the mitogen-activated protein kinase Sty1-driven signaling cascade activates hundreds of genes to induce a robust anti-stress cellular response in fission yeast. Thus, upon stress imposition Sty1 transiently accumulates in the nucleus where it up-regulates transcription through the Atf1 transcription factor. Several regulators of transcription and translation have been identified as important to mount an integral response to oxidative stress, such as the SptAda-Gcn5-acetyl transferase or Elongator complexes, respectively. With the aim of identifying new regulators of this massive gene expression program, we have used a GFP-based protein reporter and screened a fission yeast deletion collection using flow cytometry. We find that the levels of catalase fused to GFP, both before and after a threat of peroxides, are altered in hundreds of strains lacking components of chromatin modifiers, transcription complexes, and modulators of translation. Thus, the transcription elongation complex Paf1, the histone methylase Set1-COMPASS, and the translation-related Trm112 dimers are all involved in full expression of Ctt1-GFP and in wild-type tolerance to peroxides.Cells adapt to changing environments by activating signaling pathways and modifying the cellular gene expression programs. Often, those signals are stressful and transiently or permanently halt cell growth. In particular, reactive oxygen species such as hydrogen peroxide (H 2 O 2 ) trigger what is known as oxidative stress. In fission yeast, Ͼ550 types of transcripts are up-regulated Ͼ2-fold in response to peroxides, and the expression of up to 450 genes is down-regulated also by Ͼ2-fold (1). This severe change in the Schizosaccharomyces pombe transcriptome is ruled by the mitogen-activated protein kinase Sty1-driven signaling cascade, which becomes activated upon different stress signals such as H 2 O 2 to allow adaptation and survival.Upon activation, Sty1 accumulates in the nucleus and orchestrates this massive change in the cell gene expression program. The downstream transcription factor Atf1 is important for this response. Atf1 is phosphorylated by Sty1 in a stressdependent manner, and transcription of genes occurs. We and others have demonstrated that the SAGA 4 complex is recruited to stress genes in a Sty1-and Atf1-dependent manner (2, 3) and participate in chromatin remodeling along stress open reading frames to allow RNA polymerase II (Pol II) initiation and elongation.For this dramatic change in the gene expression program to occur, not only the Pol II transcriptional machinery but also the translation process of the newly induced stress mRNAs has to be coordinated (4) and also be robust. Thus, we recently described that mutations in Elongator components impair wild-type tolerance to peroxides, probably by decreasing the amount of proteins synthesized from the stress mRNAs (5). Elongator introduces a modification of the anticodon loop of the low copy number tRNA UUU Lys as well as in other two types of tRNAs with a urac...

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“…2,[49][50][51] Moreover, DNA damage and replication failure can stimulate the activation of yeast cell death programs; 52 oxygen metabolism and ROS generation are thereby major causes of DNA damages. In yeast, several players involved in DNA-damage-regulated apoptosis have been found, including tRNA methyltransferase-9, which acts as a tRNA modifier that positively regulates the expression levels of major DNA-damage-response proteins, 53 or the peroxiredoxin Tsa1p, identified as a key peroxidase able to suppress genome instability. 54 Genomic instability, which contributes to aging in all eukaryotes, is intimately related to replication stress, which in yeast affects both chronological and replicative aging.…”

Section: Triggering Yeast Apoptosismentioning

confidence: 99%

Apoptosis in yeast: triggers, pathways, subroutines

et al. 2010

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A cell's decision to die is controlled by a sophisticated network whose deregulation contributes to the pathogenesis of multiple diseases including neoplastic and neurodegenerative disorders. The finding, more than a decade ago, that baker's yeast (Saccharomyces cerevisiae) can undergo apoptosis uncovered the possibility to investigate this mode of programmed cell death (PCD) in a model organism that combines both technical advantages and a eukaryotic 'cell room.' Since then, numerous exogenous and endogenous triggers have been found to induce yeast apoptosis and multiple yeast orthologs of crucial metazoan apoptotic regulators have been identified and characterized at the molecular level. Such apoptosis-relevant orthologs include proteases such as the yeast caspase as well as several mitochondrial and nuclear proteins that contribute to the execution of apoptosis in a caspase-independent manner. Additionally, physiological scenarios such as aging and failed mating have been discovered to trigger apoptosis in yeast, providing a teleological interpretation of PCD affecting a unicellular organism. Due to its methodological and logistic simplicity, yeast constitutes an ideal model organism that is efficiently helping to decipher the cell death regulatory network of higher organisms, including the switches between apoptotic, autophagic, and necrotic pathways of cellular catabolism. Here, we provide an overview of the current knowledge about the apoptotic subroutine of yeast PCD and its regulation.

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Trm9-Catalyzed tRNA Modifications Link Translation to the DNA Damage Response

Cited by 289 publications

References 36 publications

The conserved Wobble uridine tRNA thiolase Ctu1–Ctu2 is required to maintain genome integrity

The conserved Wobble uridine tRNA thiolase Ctu1–Ctu2 is required to maintain genome integrity

Genome-wide Screening of Regulators of Catalase Expression

Apoptosis in yeast: triggers, pathways, subroutines

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