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ENZYMES THAT CATALYZE WOBBLE Trna MODIFICATION PROMOTE MELANOMAGENESIS Aberrant Mrna Translation Can Promote Tumo- but Rapidly Develop Acquired Resistance

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ENZYMES THAT CATALYZE WOBBLE Trna MODIFICATION PROMOTE MELANOMAGENESIS Aberrant Mrna Translation Can Promote Tumo- but Rapidly Develop Acquired Resistance Published OnlineFirst June 29, 2018; DOI: 10.1158/2159-8290.CD-RW2018-109 RESEARCH WATCH Transcription Major finding: Low-complexity domains Concept: Transcription factor LCD Impact: Rapid, reversible LCD–LCD in- (LCD) in transcription factors can form hubs stabilize DNA binding and recruit teractions may represent a fundamental high-concentration interaction hubs. RNA Pol II to activate transcription. mechanism of transcriptional control. TRANSCRIPTION FACTOR LOW-COMPLEXITY DOMAIN HUBS DRIVE TRANSCRIPTION Although many transcription factors have well-structured could be disrupted by 1,6-hexanediol, a chemical that dissolves DNA binding domains, their transactivation domains often various intracellular membrane-less compartments. Although harbor low-complexity sequence domains (LCD) that adopt LCD–LCD interactions could form independent of DNA, tran- an intrinsically disordered conformation, hampering conven- scription factor–DNA interactions maintained a high local tional structural determination and pharmacologic targeting. concentration of transcription factor LCDs, stabilizing both Mutations in transcription factor LCDs have been implicated LCD–LCD interactions and transcription factor–DNA interac- in transcriptional disruption and cancer. However, it is unclear tions. EWS–FLI1, a fusion protein that drives Ewing sarcoma how transcription factor LCDs drive transactivation. Chong tumorigenesis, harbors an LCD and binds to GGAA microsat- and colleagues used high-resolution imaging strategies to char- ellites in the human genome. The EWS LCD–LCD interactions acterize the dynamic behavior of transcription factor LCDs at facilitated formation of EWS–FLI1 hubs at GGAA microsatel- target genomic loci under physiologic conditions. Integrating lite DNA elements in Ewing sarcoma cells, and were required a synthetic Lac operator array into cells that express various for the EWS–FLI1-mediated transcriptional activation to drive tagged transcription factor LCDs fused to LacI resulted in oncogenic gene expression. Although liquid–liquid phase sepa- LacO array recruitment of a large number of LCD–LacI mol- ration was detected with gross overexpression of LCDs, it was ecules via targeted DNA binding, forming concentrated local not detected for the functional EWS LCD interaction hubs LCD interaction hubs in the nucleus. Further, LCD–LCD formed at native genomic loci in the presence of endogenous interactions could occur even without binding to DNA, indi- EWS–FLI1. Collectively, these fi ndings reveal a mechanism by cating the ability of LCD hubs to self-assemble. LCD–LCD which transcription factor LCDs may drive transcription. I interactions stabilized transcription factor binding to DNA, and LCD hubs could interact with RNA polymerase II (Pol Chong S, Dugast-Darzacq C, Liu Z, Dong P, Dailey GM, Cattoglio C, II), a key step in transactivation. The LCD–LCD interactions et al. Imaging dynamic and selective low-complexity domain interactions were sequence-specifi c, highly dynamic, and reversible, and that control gene transcription. Science 2018 Jun 21 [Epub ahead of print]. Translation Major finding: Enzymes that modify wob- Concept: U34 enzymes promote glycol- Impact: U34 enzyme upregulation in V600E ble uridine 34 tRNAs (U34 enzymes) main- ysis through direct, codon-dependent patients with BRAF may be a mech- tain HIF1α levels in BRAFV600E melanoma. regulation of HIF1A translation. anism of resistance to RAF inhibitors. ENZYMES THAT CATALYZE WOBBLE tRNA MODIFICATION PROMOTE MELANOMAGENESIS Aberrant mRNA translation can promote tumo- but rapidly develop acquired resistance. Analysis rigenesis and drug resistance, but the molecular of data from The Cancer Genome Atlas revealed mechanisms have not been fully elucidated. Wobble that U34 enzymes were upregulated in patients who tRNA modifi cations are essential for the transla- had acquired resistance to the RAF inhibitor vemu- tion of specifi c codons, and the enzymes that carry rafenib, and increased expression of U34 enzymes out the modifi cations of wobble uridine 34 tRNA was also linked to increased HIF1α levels, suggesting (U34 enzymes) were shown to be upregulated in that U34 enzymes may be associated with resist- BRAFV600E melanoma cells in zebrafi sh. Rapino and ance to RAF inhibitors in patients with BRAFV600E colleagues found that the U34 enzymes ELP1, ELP3, and CTU2 melanoma. Moreover, U34 enzyme depletion resensitized vemu- were also upregulated in human melanomas and melanoma rafenib-resistant BRAFV600E cells to RAF inhibition. In vivo, cell lines, indicating a potential role for U34 tRNA modifi cation inhibition of ELP3 or CTU2 sensitized resistant melanoma in BRAFV600E melanomagenesis. The HIF1A mRNA sequence xenografts to vemurafenib. Activation of PI3K signaling, which is enriched for codons that require U34 tRNA modifi cations, is one mechanism of resistance to RAF inhibition, increased U34 suggesting that it requires U34 enzymes for accurate translation. enzyme levels, elucidating a potential role for U34 enzymes in Indeed, the U34 enzymes promoted codon-dependent regula- drug resistance. In addition to demonstrating that U34 enzymes tion of HIF1A translation, thereby increasing HIF1α levels to maintain HIF1α levels, these fi ndings suggest a role for U34 promote glycolytic gene expression in BRAFV600E melanoma enzymes in melanoma progression and drug resistance. I cells and reducing the dependence on the tricarboxylic acid cycle. Further, HIF1α loss phenocopied U34 enzyme loss of Rapino F, Delaunay S, Rambow F, Zhou Z, Tharun L, De Tullio P, function and reduced the survival of BRAFV600E cells. Patients et al. Codon-specifi c translation reprogramming promotes resistance with BRAFV600E melanoma often respond to RAF inhibitors, to targeted therapy. Nature 2018;558:605–9. 910 | CANCER DISCOVERYAUGUST 2018 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst June 29, 2018; DOI: 10.1158/2159-8290.CD-RW2018-109 Enzymes That Catalyze Wobble tRNA Modification Promote Melanomagenesis Cancer Discov 2018;8:910. Published OnlineFirst June 29, 2018. Updated version Access the most recent version of this article at: doi:10.1158/2159-8290.CD-RW2018-109 E-mail alerts Sign up to receive free email-alerts related to this article or journal. Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected]. Permissions To request permission to re-use all or part of this article, use this link http://cancerdiscovery.aacrjournals.org/content/8/8/910.2. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site. Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2018 American Association for Cancer Research. .
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