The WD-repeat protein GRWD1: Potential roles in myeloid differentiation and ribosome biogenesis

Gratenstein, Kim; Heggestad, Arnold D.; Fortun, Jenny; Notterpek, Lucia; Pestov, Dimitri G.; Fletcher, Bradley S.

doi:10.1016/j.ygeno.2005.02.010

Cited by 33 publications

(32 citation statements)

References 42 publications

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“…3A). Interestingly, we also detected U3snoRNA, a small nucleolar RNA implicated in early pre-rRNA cleavage and 40S subunit assembly (36), consistent with the observation that Ku interacts with proteins involved in ribosomal RNA processing (the guanine nucleotide binding protein-like 3, GNL3, and NOP2) (37,38) and ribosomal biogenesis (the biogenesis of ribosomes in Xenopus protein BRIX and the glutamate-rich WD repeat containing protein1, GRWD1) (supplemental Table S3 Peptide Data for Replicate Analyses of Ku Complex) (39,40). These results demonstrate that both ribosomal RNAs and ribosomal proteins specifically associate with Ku in intact cells.…”

Section: Uv Radiation Induces Changes In the Localization Of A Subsetsupporting

confidence: 72%

DNA Ends Alter the Molecular Composition and Localization of Ku Multicomponent Complexes

Adelmant

Calkins

Garg

et al. 2012

Molecular & Cellular Proteomics

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The Ku heterodimer plays an essential role in non-homologous end-joining and other cellular processes including transcription, telomere maintenance and apoptosis. While the function of Ku is regulated through its association with other proteins and nucleic acids, the specific composition of these macromolecular complexes and their dynamic response to endogenous and exogenous cellular stimuli are not well understood. Here we use quantitative proteomics to define the composition of Ku multicomponent complexes and demonstrate that they are dramatically altered in response to UV radiation. The Ku heterodimer (hereafter referred to as "Ku") is composed of 70 kDa (Ku70) and 86 kDa (Ku86) subunits that associate in stoichiometric quantities and bind DNA ends with high affinity as a first step in the nonhomologous end-joining DNA repair pathway. Ku binding to double strand breaks results in recruitment of the catalytic subunit of DNA-dependent protein kinase DNA-PKcs to form the holo-enzyme DNA-PK, followed by the exonuclease Artemis and the XRCC4-like factor XLF (1). The final stage of repair requires polymerase activity and the ligation of the DNA ends by a complex composed of the x-ray repair cross-complementing protein XRCC4 and DNA-ligase-IV (2-4). In addition to its DNA-directed activities, Ku and DNA-PKcs are known to regulate other cellular functions such as RNA-transcription (5-11), processing (12, 13) and telomere maintenance (12,14).The functional diversity of Ku suggests that its cellular activities are regulated by distinct sets of molecular interactions. To date, Ku protein partners include the RNA helicase RHA and several heterogeneous ribonucleoproteins (13), the Werner Syndrome associated protein WRN (15-17), poly-(ADP-ribose) polymerase I PARP-1 (17, 18), the yin-yang transcription factor YY1 (19), histone H2AX (20), and telomerase (12,14). Binary protein-protein interactions with Ku70 were also delineated by two-hybrid screen (21), whereas mass spectrometry-based approaches have been used to identify multicomponent protein complexes that copurify with Ku (22,23). These data provide a useful inventory of Ku protein partners, although the dynamics of specific interactions in response to exogenous or endogenous stimuli remain unknown. In addition, the mechanisms by which Ku selectively engages with DNA versus RNA and whether these nucleic acid interactions are dependent on Ku protein associations, is largely unexplored. Finally, although Ku resides in distinct nuclear compartments (24,25), the relationship between Ku localization and the molecular composition of its associated macromolecular complex is unresolved.In this study, we used biochemical and proteomics approaches to delineate Ku molecular interactions, localization, and dynamic response to DNA damage. Ultraviolet (UV) irradiation resulted in the recruitment of DNA-binding proteins to the multi-component Ku complex and a concomitant loss of RNA-binding proteins. Addition of DNA ends to the Ku complex in vitro induced the loss of RNA-mediated pro...

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Section: Uv Radiation Induces Changes In the Localization Of A Subsetsupporting

confidence: 72%

DNA Ends Alter the Molecular Composition and Localization of Ku Multicomponent Complexes

Adelmant

Calkins

Garg

et al. 2012

Molecular & Cellular Proteomics

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“…Among other functions, SGK can regulate the expression and activities of multiple transport proteins (41). GRWD1, a homologue of a yeast protein that mediates ribosome biogenesis, stimulates growth and global protein synthesis in mammalian cells (42). The type 2 iodothyronine deiodinase (DIO2) enhances thyroid hormone receptor (TR) activity through conversion of T4 to the more potent T3 and is one of several TR-related genes increased by DHT (Table 3).…”

Section: Resultsmentioning

confidence: 99%

Androgens Induce Prostate Cancer Cell Proliferation through Mammalian Target of Rapamycin Activation and Post-transcriptional Increases in Cyclin D Proteins

Chen²,

Ross³

et al. 2006

Cancer Research

256

231

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Androgen receptor (AR) plays a central role in prostate cancer, with most tumors responding to androgen deprivation therapies, but the molecular basis for this androgen dependence has not been determined. Androgen [5A-dihydrotestosterone (DHT)] stimulation of LNCaP prostate cancer cells, which have constitutive phosphatidylinositol 3-kinase (PI3K)/ Akt pathway activation due to PTEN loss, caused increased expression of cyclin D1, D2, and D3 proteins, retinoblastoma protein hyperphosphorylation, and cell cycle progression. However, cyclin D1 and D2 message levels were unchanged, indicating that the increases in cyclin D proteins were mediated by a post-transcriptional mechanism. This mechanism was identified as mammalian target of rapamycin (mTOR) activation. DHT treatment increased mTOR activity as assessed by phosphorylation of the downstream targets p70 S6 kinase and 4E-BP1, and mTOR inhibition with rapamycin blocked the DHT-stimulated increase in cyclin D proteins. Significantly, DHT stimulation of mTOR was not mediated through activation of the PI3K/Akt or mitogen-activated protein kinase/p90 ribosomal S6 kinase pathways and subsequent tuberous sclerosis complex 2/tuberin inactivation or by suppression of AMP-activated protein kinase. In contrast, mTOR activation by DHT was dependent on ARstimulated mRNA synthesis. Oligonucleotide microarrays showed that DHT-stimulated rapid increases in multiple genes that regulate nutrient availability, including transporters for amino acids and other organic ions. These results indicate that a critical function of AR in PTEN-deficient prostate cancer cells is to support the pathologic activation of mTOR, possibly by increasing the expression of proteins that enhance nutrient availability and thereby prevent feedback inhibition of mTOR. (Cancer Res 2006; 66(15): 7783-92)

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“…Interestingly, METTL18 has been found in a complex with human RPL3 and GRWD1 in HEK293 cells (79). GRWD1 is found in pre-ribosomal complexes (80), suggesting that the human complex may have a similar function in ribosome biogenesis as the yeast enzyme. A mammalian enzyme that catalyzes the methylation of the π-nitrogen of the histidine residue in the dipeptide carnosine (β-L-Ala-L-His) to form anserine has been recently described (81).…”

Section: Protein Histidine Methyltransferasesmentioning

confidence: 99%

The ribosome: A hot spot for the identification of new types of protein methyltransferases

Clarke¹

2018

Journal of Biological Chemistry

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Cellular physiology depends on the alteration of protein structures by covalent modification reactions. Using a combination of bioinformatic, genetic, biochemical, and mass spectrometric approaches, it has been possible to probe ribosomal proteins from the yeast Saccharomyces cerevisiae for posttranslationally methylated amino acid residues and for the enzymes that catalyze these modifications. These efforts have resulted in the identification and characterization of the first protein histidine methyltransferase, the first N-terminal protein methyltransferase, two unusual types of protein arginine methyltransferases, and a new type of cysteine methylation. Two of these enzymes may modify their substrates during ribosomal assembly because the final methylated histidine and arginine residues are buried deep within the ribosome with contacts only with RNA. Two of these modifications occur broadly in eukaryotes, including humans, while the others demonstrate a more limited phylogenetic range. Analysis of strains where the methyltransferase genes are deleted has given insight into the physiological roles of these modifications. These reactions described here add diversity to the modifications that generate the typical methylated lysine and arginine residues previously described in histones and other proteins. Regulation of biological function by protein methylation reactionsIt is more and more apparent just how much of biological function is dependent upon posttranslational modifications (1). The human genome encodes some 900 enzymes catalyzing just protein phosphorylation or ubiquitination (2,3). However, it is now clear that methyl groups can stand beside phosphate groups and ubiquitin as major players in controlling the physiological functions of proteins. We are beginning to understand how the much greater diversity of protein methylation reactions can give rise to a greater diversity of function (1,4-8). We are also learning the importance of crosstalk between protein and DNA methylation reactions (9) and among protein methylation, phosphorylation, acetylation, and ubiquitination reactions (10-12). Finally, we are discovering how alterations in protein methylation pathways can lead to human pathology, particularly in cancer (13-15).The collection of over sixty human protein arginine and lysine methyltransferases that leave histone "marks" recognized by reader proteins to guide gene expression are perhaps the poster children for the importance of protein methyltransferases (16-17). However, recent work has emphasized the importance of methylating non-histone substrates at these residues, particularly ribosomal proteins, translation factors, and transcription factors in a wide variety of organisms (7,8,15,18,19). Furthermore, the methylation of lysine and arginine residues represents just the tip of the iceberg in protein methylation -modifications have also been established at histidine, modified histidine (diphthamide), glutamate, glutamine, asparagine, Lisoaspartate, D-aspartate, cysteine, isoprenylcysteine, me...

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The WD-repeat protein GRWD1: Potential roles in myeloid differentiation and ribosome biogenesis

Cited by 33 publications

References 42 publications

DNA Ends Alter the Molecular Composition and Localization of Ku Multicomponent Complexes

DNA Ends Alter the Molecular Composition and Localization of Ku Multicomponent Complexes

Androgens Induce Prostate Cancer Cell Proliferation through Mammalian Target of Rapamycin Activation and Post-transcriptional Increases in Cyclin D Proteins

The ribosome: A hot spot for the identification of new types of protein methyltransferases

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