3 The Minute Genes in Drosophila and Their Molecular Functions

Lambertsson, Andrew

doi:10.1016/s0065-2660(08)60142-x

Cited by 216 publications

(219 citation statements)

References 190 publications

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“…It is known that mutations in ribosomal proteins can provoke growth defects in Drosophila, such as those observed after Sud1 knockdown (26,27). Consistent with this, in refs.…”

Section: Sudestada1supporting

confidence: 67%

Sudestada1, a Drosophila ribosomal prolyl-hydroxylase required for mRNA translation, cell homeostasis, and organ growth

Katz

Acevedo

Loenarz

et al. 2014

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

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Genome sequences predict the presence of many 2-oxoglutarate (2OG)-dependent oxygenases of unknown biochemical and biological functions in Drosophila. Ribosomal protein hydroxylation is emerging as an important 2OG oxygenase catalyzed pathway, but its biological functions are unclear. We report investigations on the function of Sudestada1 (Sud1), a Drosophila ribosomal oxygenase. As with its human and yeast homologs, OGFOD1 and Tpa1p, respectively, we identified Sud1 to catalyze prolyl-hydroxylation of the small ribosomal subunit protein RPS23. Like OGFOD1, Sud1 catalyzes a single prolyl-hydroxylation of RPS23 in contrast to yeast Tpa1p, where Pro-64 dihydroxylation is observed. RNAi-mediated Sud1 knockdown hinders normal growth in different Drosophila tissues. Growth impairment originates from both reduction of cell size and diminution of the number of cells and correlates with impaired translation efficiency and activation of the unfolded protein response in the endoplasmic reticulum. This is accompanied by phosphorylation of eIF2α and concomitant formation of stress granules, as well as promotion of autophagy and apoptosis. These observations, together with those on enzyme homologs described in the companion articles, reveal conserved biochemical and biological roles for a widely distributed ribosomal oxygenase.fruit fly | ribosome | dioxygenase | proline | tranlational stress I ron [Fe(II)]-and 2-oxoglutarate (2OG)-dependent oxygenases are a superfamily with diverse biochemical and biological functions. During 2OG oxygenase catalysis, substrate oxidation is coupled to decarboxylation of 2OG, yielding succinate and carbon dioxide (1, 2). Structural studies reveal that the catalytic domain of 2OG oxygenases contains a conserved double-stranded β-helix (DSBH) fold presenting an HXD. . .H facial triad motif that coordinates an Fe(II) cofactor (3, 4). These and other structural features have been used to predict the existence of multiple uncharacterized 2OG oxygenases. In contrast to microorganisms and plants where 2OG oxygenases catalyze a wide variety of oxidative reactions, in animals their biochemical activities appear limited to hydroxylations or demethylations via hydroxylation (1,5,6). Despite progress in making biochemical assignments, the physiological roles of most 2OG oxygenases predicted by bioinformatic analysis of animal genomes are unknown. For instance, we have identified ∼50 putative 2OG oxygenases in the Drosophila genome, but only a few are characterized (7,8).The function of Fatiga, the single Drosophila homolog of human hypoxia inducible transcription factor (HIF) prolyl-4-hydroxylases (PHDs), has been well studied in the context of oxygen sensing (9). HIF prolyl-hydroxylation plays a central role in the animal hypoxic response via hydroxylation of HIF, a posttranslational modification that signals for HIF-α degradation in a physiologically relevant oxygen-dependent manner (10, 11). Given the tractability of these enzymes as targets for pharmacological modulation by 2OG analogs and related co...

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“…It is known that mutations in ribosomal proteins can provoke growth defects in Drosophila, such as those observed after Sud1 knockdown (26,27). Consistent with this, in refs.…”

Section: Sudestada1supporting

confidence: 67%

Sudestada1, a Drosophila ribosomal prolyl-hydroxylase required for mRNA translation, cell homeostasis, and organ growth

Katz

Acevedo

Loenarz

et al. 2014

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

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“…These phenotypes resemble those of fruitfly Minute mutants, human Diamond-Blackfan anemia patients and the mouse Bst mutant, all of which bear mutations in ribosomal protein genes 18,20,21 . Compared with other model organisms, such as fruitflies, few viable mutants of ribosomal protein genes have been detected in mice and humans, suggesting that mammals may be less able to compensate for partial loss of function of genes involved in ribosome maturation and function 18,20 . Consistent with this idea, worms and fission yeast lacking eri-1 are viable, whereas in inbred C57BL/6 mice Eri1 deficiency was associated with perinatal lethality.…”

Section: Discussionmentioning

confidence: 91%

Mouse Eri1 interacts with the ribosome and catalyzes 5.8S rRNA processing

Ansel

Pastor

Rath

et al. 2008

Nat Struct Mol Biol

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Eri1 is a 3′-to-5′ exoribonuclease conserved from fission yeast to humans. Here we show that Eri1 associates with ribosomes and ribosomal RNA (rRNA). Ribosomes from Eri1-deficient mice contain 5.8S rRNA that is aberrantly extended at its 3′ end, and Eri1, but not a catalytically inactive mutant, converts this abnormal 5.8S rRNA to the wild-type form in vitro and in cells. In human and murine cells, Eri1 localizes to the cytoplasm and nucleus, with enrichment in the nucleolus, the site of preribosome biogenesis. RNA binding residues in the Eri1 SAP and linker domains promote stable association with rRNA and thereby facilitate 5.8S rRNA 3′ end processing. Taken together, our findings indicate that Eri1 catalyzes the final trimming step in 5.8S rRNA processing, functionally and spatially connecting this regulator of RNAi with the basal translation machinery.

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“…Studies in D. melanogaster indicate that nucleolar proteins involved in ribosome assembly appear critical for maintaining cell and organismal size. Thirteen of the Drosophila minute loci associated with small body size and short bristles arise from mutations to ribosomal genes (43). Partial loss of function of the gene mfl, which encodes a ubiquitous nucleolar protein that participates in ribosomal RNA processing and pseudouridylation, results in minifly, yet another small Drosophila mutant (44).…”

Section: Discussionmentioning

confidence: 99%