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DOT1L O-GlcNAcylation promotes its protein stability and MLL-fusion leukemia cell proliferation
- Source :
- Cell Reports, Vol 36, Iss 12, Pp 109739-(2021)
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- Summary: Histone lysine methylation functions at the interface of the extracellular environment and intracellular gene expression. DOT1L is a versatile histone H3K79 methyltransferase with a prominent role in MLL-fusion leukemia, yet little is known about how DOT1L responds to extracellular stimuli. Here, we report that DOT1L protein stability is regulated by the extracellular glucose level through the hexosamine biosynthetic pathway (HBP). Mechanistically, DOT1L is O-GlcNAcylated at evolutionarily conserved S1511 in its C terminus. We identify UBE3C as a DOT1L E3 ubiquitin ligase promoting DOT1L degradation whose interaction with DOT1L is susceptible to O-GlcNAcylation. Consequently, HBP enhances H3K79 methylation and expression of critical DOT1L target genes such as HOXA9/MEIS1, promoting cell proliferation in MLL-fusion leukemia. Inhibiting HBP or O-GlcNAc transferase (OGT) increases cellular sensitivity to DOT1L inhibitor. Overall, our work uncovers O-GlcNAcylation and UBE3C as critical determinants of DOT1L protein abundance, revealing a mechanism by which glucose metabolism affects malignancy progression through histone methylation.
- Subjects :
- MLL
Methyltransferase
QH301-705.5
Histone lysine methylation
Acylation
Ubiquitin-Protein Ligases
histone
N-Acetylglucosaminyltransferases
General Biochemistry, Genetics and Molecular Biology
Cell Line
Histones
O-GlcNAcylation
Ubiquitin
Histone methylation
Humans
RNA, Small Interfering
glucose
Biology (General)
Myeloid Ecotropic Viral Integration Site 1 Protein
Cell Proliferation
Homeodomain Proteins
Leukemia
biology
Protein Stability
Chemistry
Ubiquitination
Hexosamines
Histone-Lysine N-Methyltransferase
DOT1L
Methylation
Cell biology
Ubiquitin ligase
Histone
Mutagenesis, Site-Directed
biology.protein
RNA Interference
methylation
Myeloid-Lymphoid Leukemia Protein
Subjects
Details
- ISSN :
- 22111247
- Volume :
- 36
- Database :
- OpenAIRE
- Journal :
- Cell Reports
- Accession number :
- edsair.doi.dedup.....16d6f654b62088430f300ae56f0d91d1