Histone-lysine N-methyltransferase DOT1L (DOT1L)

Histone-lysine N-methyltransferase DOT1L (DOT1L) is the sole enzyme that catalyzes mono-, di-, and tri-methylation of histone H3 at lysine 79 (H3K79), a modification occurring exclusively on nucleosomal histones and associated with active gene transcription, particularly during elongation. This mark regulates diverse processes including cell cycle progression through G1/S, mitosis, and meiosis; DNA damage response and repair; heterochromatin formation; embryonic development; and somatic cell reprogramming. DOT1L interacts with complexes like the super elongation complex and relies on upstream events such as H2B ubiquitination for optimal activity, while competing with silencing factors like Sir proteins. In disease, aberrant DOT1L activity drives leukemogenesis via recruitment by MLL fusion proteins (e.g., MLL-AF9), leading to enhanced H3K79 methylation, open chromatin maintenance, and oncogene overexpression in leukemia; it also promotes solid tumor progression, epithelial-to-mesenchymal transition, stemness, and chemoresistance in cancers like breast and ovarian. DOT1L is a validated therapeutic target, with small-molecule inhibitors like pinometostat (EPZ-5676) in clinical trials for MLL-rearranged leukemia, blocking H3K79 methylation and tumor growth, though challenges include catalytic-independent roles in cell fate and potential developmental toxicities. Overall, DOT1L exemplifies how histone modifications orchestrate chromatin dynamics critical for normal physiology and oncogenesis.

Other names

DOT1-like histone lysine methyltransferaseDot1/DOT1Ldisruptor of telomeric silencing 1-like

Inhibition of histone H3K79 methylation, Reduction of H3K79 mono-, di-, and tri-methylation, Disruption of DOT1L interaction with MLL fusion proteins, Suppression of oncogene overexpression