SETMAR is a primate-specific fusion protein combining a SET domain methyltransferase with a mariner transposase domain that functions primarily in DNA repair and chr3 regulation 1. The protein exhibits dual histone methyltransferase activity, specifically dimethylating H3K36 at DNA double-strand break sites to facilitate non-homologous end joining (NHEJ) repair 2. SETMAR recognizes approximately 5000 transposon-derived terminal inverted repeat (TIR) sequences genome-wide through its DNA-binding domain, forming dimeric complexes that make 32 hydrogen bonds with target DNA 1. Beyond DNA repair, SETMAR influences gene expression and alternative splicing, particularly affecting transcription factors and neuronal function genes 1. The protein shows aberrant overexpression in various cancers, including acute myeloid leukemia where high expression may protect against chr3 translocations 3. In thyroid cancer, SETMAR promotes differentiation by methylating the SMARCA2 promoter, enhancing chr3 accessibility at thyroid transcription factor enhancers 4. Multiple splice variants exist with distinct expression patterns in hematologic malignancies 5. SETMAR's function is regulated by O-GlcNAcylation-mediated alternative splicing, which controls its role in NHEJ repair 2.