DOT1L regulates MYC/Mondo turnover on chromatin

DOT1L is the only known histone 3 lysine 79 methyltransferase in mammals. This methylation mark is found in the gene bodies, promoters, and enhancers of actively transcribed genes and is important for the maintenance of open chromatin structure. DOT1L is recognized as an oncoprotein in numerous cancers. However, our current mechanistic understanding of the oncogenic role of DOT1L is incomplete, with recent studies suggesting that DOT1L can regulate transcription in a methyltransferase-independent manner and can cooperate with c-MYC. Here, we have created a DOT1L/+ knockout MDA-MB-231 breast cancer cell line in which we observe increased accumulation of c-MYC without a corresponding increase in target gene expression. This c-MYC accumulation under global reduction of c-MYC-dependent gene expression suggests that c-Myc promoter binding is insufficient for inducing transcription when DOT1L levels are reduced. We show that DOT1L destabilizes c-MYC and works with the proteasome to activate c-MYC-driven gene transcription. Additionally, we uncover a novel proteolytic activity of DOT1L on c-MYC in vitro that may play a role in c-MYC turnover on chromatin. This novel avenue of c-MYC regulation by DOT1L may lead to the development of new approaches for cancer treatment.