DOT1L

Disruptor of telomeric silencing 1-like (DOT1L) is the sole histone H3 lysine 79 (H3K79) methyltransferase in mammalian cells, catalyzing mono-, di-, and tri-methylation that regulates chromatin structure and gene expression^[1][2]. Mechanistically, DOT1L contributes to transcriptional initiation by recruiting general transcription factors, including TBP and TFIIA, and facilitates RNA polymerase II occupancy at promoters^[3][2]. Beyond transcription, DOT1L-mediated H3K79 methylation maintains genomic stability, regulates the cell cycle, and supports DNA damage response in multiple tissues^[4][2][5]. In hematopoietic progenitors, DOT1L primarily acts as a transcriptional repressor, with deficiency leading to impaired erythropoiesis and cell cycle arrest^[5][1]. Compared with related isoforms in lower eukaryotes, mammalian DOT1L performs both methyltransferase-dependent and independent functions, whereas kinetoplastid DOT1A and DOT1B display distinct substrate preferences and methylation kinetics^[6][7]. DOT1L has critical roles in disease models: it sustains leukemic transformation in MLL-rearranged leukemia, regulates ovarian cancer stem cell self-renewal via β-catenin signaling, and influences cardiac and renal development^{[1][8][9][10]}. Small-molecule inhibitors such as EPZ-5676 selectively target DOT1L, reducing H3K79 methylation, impairing cancer stem cell function, and offering therapeutic potential in both hematologic and solid malignancies^[8][11][3]. These inhibitors enable experimental modulation of DOT1L activity, providing insights into lineage-specific gene regulation and epigenetic control of cell identity^[12][3].