Abstract
The organization of eukaryotic genomes into chromatin provides challenges for the cell to accomplish basic cellular functions, such as transcription, DNA replication and repair of DNA damage. Accordingly, a range of proteins modify and/or read chromatin states to regulate access to chromosomal DNA. Yeast Dot1 and the mammalian homologue DOT1L are methyltransferases that can add up to three methyl groups to histone H3 lysine 79 (H3K79). H3K79 methylation is implicated in several processes, including transcription elongation by RNA polymerase II, the DNA damage response and cell cycle checkpoint activation. DOT1L is also an important drug target for treatment of mixed lineage leukemia (MLL)-rearranged leukemia where aberrant transcriptional activation is promoted by DOT1L mislocalisation. This review summarizes what is currently known about the role of Dot1/DOT1L and H3K79 methylation in transcription and genomic stability.
Highlights
Chromatin is the DNA–protein complex that organises genetic information within the nuclei of eukaryotic cells
A second-generation inhibitor, EPZ5676, is currently in clinical trials for the treatment of mixed lineage leukemia (MLL)-rearranged leukemias, and while the results look promising [102], the low bioavailability of the drug is a complicating factor [103]
The mislocalisation of DOT1L activity is strongly associated with leukaemias resulting from oncogenic chromosomal translocations involving the MLL gene
Summary
Chromatin is the DNA–protein complex that organises genetic information within the nuclei of eukaryotic cells. Dot1/DOT1L (DOT1-Like) catalyse mono-, di- and tri-methylation of histone H3 lysine 79 in a non-processive manner [17,19] using S-adenosylmethionine (SAM) as a cofactor These are the only known H3K79 methyltransferases, as knockout of their genes in yeast, flies, mice and humans leads to complete loss of H3K79 methylation [13,20,21]. H2B were sufficient to directly stimulate DOT1L methyltransferase activity [28]; and structural changes to the nucleosome caused by monoubiquitination of H2BK123 that promote the methylation of H3K79 by Dot1 Some combination of these mechanisms may be operating, as they are not mutually exclusive. H3K79 demethylase would represent a considerable step towards fully understanding the role and regulation of DOT1L and its associated H3K79 methylation in biological processes
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