IDH1/IDH2 mutations in gliomas and AML produce the oncometabolite 2-hydroxyglutarate (2-HG). What is the mechanism by which 2-HG promotes oncogenesis?
- A 2-HG competitively inhibits alpha-ketoglutarate-dependent dioxygenases (TET2 demethylases, JHDM histone demethylases), causing hypermethylation and epigenetic silencing ✓
- B 2-HG activates mTOR signaling, promoting protein synthesis and cell growth
- C 2-HG directly mutates DNA by acting as a reactive electrophile that alkylates guanine bases
- D 2-HG inhibits succinate dehydrogenase, causing accumulation of succinate and HIF-1 alpha stabilisation
Correct answer: A. 2-HG competitively inhibits alpha-ketoglutarate-dependent dioxygenases (TET2 demethylases, JHDM histone demethylases), causing hypermethylation and epigenetic silencing
Explanation
2-Hydroxyglutarate structurally resembles alpha-ketoglutarate and competitively inhibits alpha-KG-dependent dioxygenases, including TET family DNA demethylases (causing DNA hypermethylation) and Jumonji domain histone demethylases (causing H3K27me3 and H3K9me3 accumulation). This creates a hypermethylator epigenetic phenotype (CpG island methylator phenotype, CIMP) that silences tumour suppressor genes. SDH-mutant tumors use succinate-mediated HIF stabilisation, but that is a distinct mechanism not related to IDH mutations.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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