Diagram showing the altered downstream signaling pathways with H3.3G34R/V mutations. Upon H3.3G34R/V mutation, JAK/STAT, NOTCH and cGAS-STING signaling pathways are aberrantly hyperactivated with the deactivation of DNA damage response. This led to a significant accumulation of DNA mutations and enhanced gene transcription that are related to cell growth, migration, immune response and metastasis in cancer cells. (Abbreviations: HR—homologous repair, NHEJ—non-homologous end joining, DDR—DNA damage response, JAK/STAT—Janus Kinase/Signal Transducer and Activator of Transcription, ATR—Serine/threonine-protein kinase, ATM—Ataxia-telangiectasia mutated kinase, NOTCH—Neurogenic locus notch homolog protein 1, NICD—NOTCH intracellular domain, cGAS-STING—Cyclic GMP–AMP Synthase/Stimulator of Interferon Genes, IRF3—Interferon regulatory factor 3, NF-κB—Nuclear factor kappa-light-chain-enhancer of activated B cells).