ArticleClinical epigenetics2019
The histone methyltransferase DOT1L is required for proper DNA damage response, DNA repair, and modulates chemotherapy responsiveness.
Article in Clinical epigenetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 74 citations in OpenAlex.
- Decreased H3K79 acetylation and dysregulation of neurodevelopmental genes in fetal down syndrome.Translational pediatrics · 2026Article
- Navigating luminal heterogeneity: etiology-based proteogenomic subtyping for targeted treatment strategies in breast cancer.Molecular cancer · 2026Article
- DOT1L Drives Endothelial-to-Mesenchymal Transition and Fibrotic Vascular Remodeling via H3K79 Methylation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Metabolic drivers of genome instability in cancer: mechanisms and therapeutic opportunities.Experimental hematology & oncology · 2026Review
- PICALM::MLLT10 translocated leukemia.FEBS letters · 2026Review
- Trans-histone crosstalk establishes distinct H3K79 methylation zones with differential transcriptional functions.Nucleic acids research · 2026Article
- DOT1L activity limits transcription elongation velocity and favors RNAPII pausing to facilitate mutagenesis by AID.Nature communications · 2026Article
- DOT1L inhibition exerts the anti-tumor effect by activating interferon signaling in breast cancer cells.Clinical epigenetics · 2025Article
- Genetic Insights into Brain Morphology: a Genome-Wide Association Study of Cortical Thickness and TNeuroinformatics · 2025Article
- TAOK1 promotes filament formation in HR repair through phosphorylating USP7.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- DOT1L Mediates Stem Cell Maintenance and Represents a Therapeutic Vulnerability in Cancer.Cancer research · 2025Review
- Transcription-replication conflicts drive R-loop-dependent nucleosome eviction and require DOT1L activity for transcription recovery.Nucleic acids research · 2025Article
- Keep calm and reboot - how cells restart transcription after DNA damage and DNA repair.FEBS letters · 2025Review
- DOT1L protects against podocyte injury in diabetic kidney disease through phospholipase C-like 1.Cell communication and signaling : CCS · 2024Article
- DOT1L-mediated RAP80 methylation promotes BRCA1 recruitment to elicit DNA repair.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- β-hydroxybutyrate resensitizes colorectal cancer cells to oxaliplatin by suppressing H3K79 methylation in vitro and in vivo.Molecular medicine (Cambridge, Mass.) · 2024Article
- PARP1-DOT1L transcription axis drives acquired resistance to PARP inhibitor in ovarian cancer.Molecular cancer · 2024Article
- An emerging maestro of immune regulation: how DOT1L orchestrates the harmonies of the immune system.Frontiers in immunology · 2024Review
- Review
- Nucleophosmin 1 cooperates with the methyltransferase DOT1L to preserve peri-nucleolar heterochromatin organization by regulating H3K27me3 levels and DNA repeats expression.Epigenetics & chromatin · 2023Article
Corrections and comments
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Authors and funding
16 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundDisruptor of telomeric silencing 1-like (DOT1L) is a non-SET domain containing methyltransferase known to catalyze mono-, di-, and tri-methylation of histone 3 on lysine 79 (H3K79me). DOT1L-mediated H3K79me has been implicated in chromatin-associated functions including gene transcription, heterochromatin formation, and DNA repair. Recent studies have uncovered a role for DOT1L in the initiation and progression of leukemia and other solid tumors. The development and availability of small molecule inhibitors of DOT1L may provide new and unique therapeutic options for certain types or subgroups of cancer.
methodsIn this study, we examined the role of DOT1L in DNA double-strand break (DSB) response and repair by depleting DOT1L using siRNA or inhibiting its methyltransferase activity using small molecule inhibitors in colorectal cancer cells. Cells were treated with different agents to induce DNA damage in DOT1L-depleted or -inhibited cells and analyzed for DNA repair efficiency and survival. Further, rectal cancer patient samples were analyzed for H3K79me3 levels in order to determine whether it may serve as a potential marker for personalized therapy.
resultsOur results indicate that DOT1L is required for a proper DNA damage response following DNA double-strand breaks by regulating the phosphorylation of the variant histone H2AX (γH2AX) and repair via homologous recombination (HR). Importantly, we show that small molecule inhibitors of DOT1L combined with chemotherapeutic agents that are used to treat colorectal cancers show additive effects. Furthermore, examination of H3K79me3 levels in rectal cancer patients demonstrates that lower levels correlate with a poorer prognosis.
conclusionsIn this study, we conclude that DOT1L plays an important role in an early DNA damage response and repair of DNA double-strand breaks via the HR pathway. Moreover, DOT1L inhibition leads to increased sensitivity to chemotherapeutic agents and PARP inhibition, which further highlights its potential clinical utility. Our results further suggest that H3K79me3 can be useful as a predictive and or prognostic marker for rectal cancer patients.
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