The histone methyltransferase DOT1L: regulatory functions and a cancer therapy target

Abstract

DOT1L is a unique histone methyltransferase that targets the histone H3 lysine 79 (H3K79) residue for mono-, di- and tri- methylation. Histone H3K79 mono- and di-methylation results in active gene transcription, while H3K79 tri-methylation is associated with gene repression. DOT1L has a critical role in regulating gene transcription, development, cell cycle progression, somatic reprogramming and DNA damage repair. DOT1L interacts with Mixed Lineage Leukemia (MLL) fusion proteins, leading to enhanced H3K79 methylation, maintenance of open chromatin, overexpression of downstream oncogenes and leukemogenesis. Importantly, small molecule DOT1L inhibitors have been recently developed, and one of the DOT1L inhibitors is already under investigation in a Phase I clinical trial in patients with MLL fusion gene-driven leukemia.

Keywords: DOT1L; DOT1L inhibitors; gene transcription; histone methylation; mixed lineage leukemia.

Figure 1

Chemical structures of DOT1L inhibitors. A. DOT1L catalyses histone H3K79 methylation by transferring a methyl group from its substrate S-adenosyl-L-methionine (SAM) to the amino group of a lysine residue on the histone. A methylated H3K79 residue and S-adeno-L-homocysteine (SAH) are produced, and DOT1L then dissociates. Additional methyl groups are added in a sequential and similar manner. B. Small molecular DOT1L inhibitors: EPZ004777, EPZ5676, SGC0946 and SYC-522. All are based on SAH backbone and target the SAM binding pocket of DOT1L.

Figure 2

Model of possible MLL-AF9 and DOT1L-mediated gene transcription mechanism in MLL-driven leukaemia. A. SUV39H1 and SIRT1 increase H3K9 methylation and decrease H3K9 acetylation, preventing MLL-AF9 and Elongation Assisting Proteins (EAP) complex binding to gene promoters. B. DOT1L inhibits SIRT1 and SUV39H1 chromatin localization, thereby maintaining an open chromatin state with elevated H3K9 acetylation and H3K79 methylation and minimal H3K9 methylation at MLL fusion protein target gene promoters. MLL-AF9 forms a protein complex with DOT1L, recognises elevated H3K9 acetylation via its YEATS domain, and recruits the EAP complex containing RNA Pol II and other transcription factors at MLL fusion protein target gene promoters, leading to transcriptional activation.