SUV39H1 is a histone lysine methyltransferase that catalyzes H3K9 trimethylation, establishing and maintaining constitutive heterochromatin through a positive feedback mechanism. HP1 proteins recognize pre-existing H3K9me3 marks and recruit SUV39H1 to methylate newly incorporated histones 1. This process is dynamically regulated: ASB7 ubiquitin ligase promotes SUV39H1 degradation to prevent excessive heterochromatin, while CDK1 phosphorylation of ASB7 during mitosis stabilizes SUV39H1 for epigenetic inheritance 1. ZNF512 and ZNF512B zinc-finger proteins specifically recruit SUV39H1 to pericentric regions to initiate de novo heterochromatin formation 2. Beyond chrX silencing, SUV39H1 methylates non-histone substrates with disease-relevant consequences. It methylates cGAS to enhance chrX sequestration and suppress antitumor immunity; methionine restriction blocks this methylation, activating cGAS-mediated antiviral responses 3. SUV39H1 represses heme oxygenase 1 (HMOX1) transcription, promoting hepatic stellate cell activation and liver fibrosis; pharmacological inhibition by chaetocin ameliorates fibrosis in mice 4. SUV39H1 function is therapeutically targetable: FBXO44/SUV39H1 inhibition reactivates repetitive elements in cancer cells, triggering DNA replication stress and viral mimicry to enhance immunotherapy response 5. SUV39H1 disruption enhances CAR T-cell persistence and antitumor efficacy by improving memory transcription factor expression while limiting exhaustion 6.