DOT1L (DOT1 Like Histone Lysine Methyltransferase) is a histone methyltransferase that specifically methylates lysine 79 of histone H3 (H3K79), with nucleosomes being preferred substrates over free histones 1. This methylation activity plays crucial roles in transcriptional regulation and DNA damage response. DOT1L functions as part of complex regulatory networks, including interactions with the MLL1 complex that can elicit conformational changes regulating transcription 2. In cancer contexts, DOT1L demonstrates significant pathological relevance. It contributes to PARP inhibitor resistance in ovarian cancer through a PARP1-DOT1L-PLCG2/ABCB1 axis, where PARP1 directly binds to the DOT1L promoter and enhances its transcription 3. DOT1L is identified as a therapeutic target in acute myeloid leukemia, with established clinical actionability 4. Additionally, DOT1L plays a critical role in DNA damage repair by methylating RAP80 at multiple lysines, which is essential for BRCA1-A complex recruitment to double-strand breaks 5. In neurodevelopment, DOT1L functions as part of an epigenetic barrier that controls the timing of human neuronal maturation 6. The enzyme's diverse roles make it a promising therapeutic target across multiple cancer types and developmental disorders.