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000291067 1001_ $$0P:(DE-HGF)0$$aKyrkou, Athena$$b0$$eFirst author
000291067 245__ $$aG6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells.
000291067 260__ $$a[London]$$bNature Publishing Group UK$$c2024
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000291067 520__ $$aNeurofibromatosis Type II (NFII) is a genetic condition caused by loss of the NF2 gene, resulting in activation of the YAP/TAZ pathway and recurrent Schwann cell tumors, as well as meningiomas and ependymomas. Unfortunately, few pharmacological options are available for NFII. Here, we undertake a genome-wide CRISPR/Cas9 screen to search for synthetic-lethal genes that, when inhibited, cause death of NF2 mutant Schwann cells but not NF2 wildtype cells. We identify ACSL3 and G6PD as two synthetic-lethal partners for NF2, both involved in lipid biogenesis and cellular redox. We find that NF2 mutant Schwann cells are more oxidized than control cells, in part due to reduced expression of genes involved in NADPH generation such as ME1. Since G6PD and ME1 redundantly generate cytosolic NADPH, lack of either one is compatible with cell viability, but not down-regulation of both. Since genetic deficiency for G6PD is tolerated in the human population, G6PD could be a good pharmacological target for NFII.
000291067 536__ $$0G:(DE-HGF)POF4-312$$a312 - Funktionelle und strukturelle Genomforschung (POF4-312)$$cPOF4-312$$fPOF IV$$x0
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000291067 650_7 $$0EC 1.1.1.49$$2NLM Chemicals$$aGlucosephosphate Dehydrogenase
000291067 650_7 $$2NLM Chemicals$$aNeurofibromin 2
000291067 650_7 $$0EC 6.2.1.-$$2NLM Chemicals$$aCoenzyme A Ligases
000291067 650_7 $$0EC 6.2.1.3$$2NLM Chemicals$$along-chain-fatty-acid-CoA ligase
000291067 650_7 $$0EC 1.1.1.49$$2NLM Chemicals$$aG6PD protein, human
000291067 650_7 $$053-59-8$$2NLM Chemicals$$aNADP
000291067 650_7 $$2NLM Chemicals$$aNF2 protein, human
000291067 650_2 $$2MeSH$$aSchwann Cells: metabolism
000291067 650_2 $$2MeSH$$aHumans
000291067 650_2 $$2MeSH$$aCRISPR-Cas Systems
000291067 650_2 $$2MeSH$$aGlucosephosphate Dehydrogenase: metabolism
000291067 650_2 $$2MeSH$$aGlucosephosphate Dehydrogenase: genetics
000291067 650_2 $$2MeSH$$aNeurofibromin 2: metabolism
000291067 650_2 $$2MeSH$$aNeurofibromin 2: genetics
000291067 650_2 $$2MeSH$$aCoenzyme A Ligases: metabolism
000291067 650_2 $$2MeSH$$aCoenzyme A Ligases: genetics
000291067 650_2 $$2MeSH$$aSynthetic Lethal Mutations
000291067 650_2 $$2MeSH$$aAnimals
000291067 650_2 $$2MeSH$$aNeurofibromatosis 2: metabolism
000291067 650_2 $$2MeSH$$aNeurofibromatosis 2: genetics
000291067 650_2 $$2MeSH$$aNADP: metabolism
000291067 650_2 $$2MeSH$$aMice
000291067 650_2 $$2MeSH$$aOxidation-Reduction
000291067 7001_ $$0P:(DE-He78)bdd94d9db11251c743b72697c246c826$$aValla, Robert$$b1$$udkfz
000291067 7001_ $$0P:(DE-He78)af5aa018fd9946298428cbbf4f08fc4f$$aZhang, Yao$$b2$$udkfz
000291067 7001_ $$0P:(DE-He78)23cd897fa1cbd5ff0abbfa997c2f20f9$$aAmbrosi, Giulia$$b3
000291067 7001_ $$0P:(DE-He78)e4106a3c510e44f92596378a8af09ba8$$aLaier, Stephanie$$b4$$udkfz
000291067 7001_ $$0P:(DE-He78)799d978330dff449f8244947929a4518$$aMüller-Decker, Karin$$b5$$udkfz
000291067 7001_ $$0P:(DE-He78)3c0da8e3caa2aa50cad85152aa0465ad$$aBoutros, Michael$$b6$$udkfz
000291067 7001_ $$0P:(DE-He78)5ebc16fd8019dbfde58e0125b001b599$$aTeleman, Aurelio$$b7$$eLast author$$udkfz
000291067 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-024-49298-7$$gVol. 15, no. 1, p. 5115$$n1$$p5115$$tNature Communications$$v15$$x2041-1723$$y2024
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