دورية أكاديمية
أعرض في EDS

G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells.

التفاصيل البيبلوغرافية
العنوان: G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells.
المؤلفون: Kyrkou A; German Cancer Research Center (DKFZ), Division B140, 69120, Heidelberg, Germany.; Heidelberg University, Institute of Human Genetics, 69120, Heidelberg, Germany., Valla R; German Cancer Research Center (DKFZ), Division B140, 69120, Heidelberg, Germany.; Heidelberg University, Institute of Human Genetics, 69120, Heidelberg, Germany., Zhang Y; German Cancer Research Center (DKFZ), Division B140, 69120, Heidelberg, Germany.; Heidelberg University, Institute of Human Genetics, 69120, Heidelberg, Germany., Ambrosi G; German Cancer Research Center (DKFZ), Div. Signaling and Functional Genomics, 69120, Heidelberg, Germany., Laier S; Core Facility Tumor Models, German Cancer Research Center (DKFZ), Heidelberg, Germany., Müller-Decker K; Core Facility Tumor Models, German Cancer Research Center (DKFZ), Heidelberg, Germany., Boutros M; Heidelberg University, Institute of Human Genetics, 69120, Heidelberg, Germany.; German Cancer Research Center (DKFZ), Div. Signaling and Functional Genomics, 69120, Heidelberg, Germany., Teleman AA; German Cancer Research Center (DKFZ), Division B140, 69120, Heidelberg, Germany. a.teleman@dkfz.de.; Heidelberg University, Institute of Human Genetics, 69120, Heidelberg, Germany. a.teleman@dkfz.de.
المصدر: Nature communications [Nat Commun] 2024 Jun 15; Vol. 15 (1), pp. 5115. Date of Electronic Publication: 2024 Jun 15.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: Schwann Cells*/metabolism , CRISPR-Cas Systems* , Glucosephosphate Dehydrogenase*/metabolism , Glucosephosphate Dehydrogenase*/genetics , Neurofibromin 2*/metabolism , Neurofibromin 2*/genetics , Coenzyme A Ligases*/metabolism , Coenzyme A Ligases*/genetics , Synthetic Lethal Mutations*, Humans ; Animals ; Neurofibromatosis 2/metabolism ; Neurofibromatosis 2/genetics ; NADP/metabolism ; Mice ; Oxidation-Reduction
مستخلص: Neurofibromatosis 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.
(© 2024. The Author(s).)
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المشرفين على المادة: EC 1.1.1.49 (Glucosephosphate Dehydrogenase)
0 (Neurofibromin 2)
EC 6.2.1.- (Coenzyme A Ligases)
EC 6.2.1.3 (long-chain-fatty-acid-CoA ligase)
EC 1.1.1.49 (G6PD protein, human)
53-59-8 (NADP)
0 (NF2 protein, human)
تواريخ الأحداث: Date Created: 20240615 Date Completed: 20240615 Latest Revision: 20240701
رمز التحديث: 20240701
مُعرف محوري في PubMed: PMC11180199
DOI: 10.1038/s41467-024-49298-7
PMID: 38879607
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-024-49298-7