Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.1.1.37 (
DNA methyltransferase
)
4,983
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Many non-histone proteins are lysine methylated and a novel function of this modification is to trigger the proteolysis of methylated proteins. Here, we report that the methylated lysine 142 of DNMT1, a major
DNA methyltransferase
that preserves epigenetic inheritance of DNA methylation patterns during DNA replication, is demethylated by LSD1. A novel methyl-binding protein,
L3MBTL3
, binds the K142-methylated DNMT1 and recruits a novel CRL4
DCAF5
ubiquitin ligase to degrade DNMT1. Both LSD1 and PHF20L1 act primarily in S phase to prevent DNMT1 degradation by
L3MBTL3
-CRL4
DCAF5
. Mouse
L3MBTL3
/MBT-1 deletion causes accumulation of DNMT1 protein, increased genomic DNA methylation, and late embryonic lethality. DNMT1 contains a consensus methylation motif shared by many non-histone proteins including E2F1, a key transcription factor for S phase. We show that the methylation-dependent E2F1 degradation is also controlled by
L3MBTL3
-CRL4
DCAF5
. Our studies elucidate for the first time a novel mechanism by which the stability of many methylated non-histone proteins are regulated.
...
PMID:Methylated DNMT1 and E2F1 are targeted for proteolysis by L3MBTL3 and CRL4
DCAF5
ubiquitin ligase. 2969 1
The Sonic hedgehog signalling is known to play a crucial role in regulating embryonic development, cancer stem cell maintenance and tissue patterning. Dysregulated hedgehog signalling has been reported to affect tumorigenesis and drug response in various human malignancies. Epigenetic therapy relying on
DNA methyltransferase
and Histone deacetylase inhibitors are being proposed as potential drug candidates considering their efficiency in preventing development of cancer progenitor cells, killing drug resistant cells and also dictating "on/off" switch of tumor suppressor genes and oncogenes. In this docking approach, epigenetic modulators were virtually screened for their efficiency in inhibiting key regulators of SHH pathway viz., sonic hedgehog, Smoothened and Gli using polypharmacological approach. The control drugs and epigenetic modulators were docked with PDB protein structures using AutoDock vina and further checked for their drug-likeness properties. Further molecular dynamics simulation using VMD and NAMD, and MMP/GBSA energy calculation were employed for verifying the stability and entropy of the ligand-receptor complex. EPZ-6438 and GSK 343 (EZH2 inhibitors), CHR 3996 and Mocetinostat (HDAC inhibitors), GSK 126 (HKMT inhibitor) and UNC 1215 (
L3MBTL3
antagonist) exhibited multiple-targeted approach in modulating HH signalling. This is the first study to report these epigenetic drugs as potential multi-targeted hedgehog pathway inhibitors. Thus, epigenetic polypharmacology approach can be explored as a better alternative to challenges of acute long term toxicity and drug resistance occurring due to traditional single targeted chemotherapy in the future.
...
PMID:Epigenetic Modulators as Potential Multi-targeted Drugs Against Hedgehog Pathway for Treatment of Cancer. 3099 46
