Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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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)
A new inhibitor of
DNA methyltransferase
named DMI-1 has been discovered in the culture filtrate of Streptomyces sp. strain No. 560. DMI-1 was purified by extraction with ethyl acetate followed by Diaion HP-20SS and silica gel column chromatography. The structure of DMI-1 was determined to be 8-methylpentadecanoic acid (
C16H32O2
). DMI-1 is a novel inhibitor of methyltransferase isolated from microorganisms and is structurally different from sinefungin and A9145C which are structural analogs of S-adenosylmethionine (methyl donor). DMI-1 was a strong inhibitor of N6-methyladenine-
DNA methyltransferase
(M. Eco RI, EC 2.1.1.72) in a noncompetitive manner and its inhibition depended on the pH and temperature in the assay media.
...
PMID:DMI-1, a new DNA methyltransferase inhibitor produced by Streptomyces sp. strain No. 560. 859 34
DNA methylation plays a critical role in the regulation and maintenance of cell-type specific transcriptional programs. Targeted epigenome editing is an emerging technology to specifically regulate cellular gene expression in order to modulate cell phenotypes or dissect the epigenetic mechanisms involved in their control. In this work, we employed a
DNA methyltransferase
Dnmt3a-Dnmt3L construct fused to the nuclease-inactivated dCas9 programmable targeting domain to introduce DNA methylation into the human genome specifically at the EpCAM, CXCR4 and TFRC gene promoters. We show that targeting of these loci with single gRNAs leads to efficient and widespread methylation of the promoters. Multiplexing of several guide RNAs does not increase the efficiency of methylation. Peaks of targeted methylation were observed around 25 bp upstream and 40 bp downstream of the
PAM
site, while 20-30 bp of the binding site itself are protected against methylation. Potent methylation is dependent on the multimerization of Dnmt3a/Dnmt3L complexes on the DNA. Furthermore, the introduced methylation causes transcriptional repression of the targeted genes. These new programmable epigenetic editors allow unprecedented control of the DNA methylation status in cells and will lead to further advances in the understanding of epigenetic signaling.
...
PMID:Efficient targeted DNA methylation with chimeric dCas9-Dnmt3a-Dnmt3L methyltransferase. 2789 45
Via extensive analyses of genetic databases, we have characterized the DNA-repair capacity of glioblastoma with respect to patient survival. In addition to elevation of O
6
-methylguanine
DNA methyltransferase
(MGMT), down-regulation of three DNA repair pathways; canonical mismatch repair (MMR), Non-Homologous End-Joining (NHEJ), and Homologous Recombination (HR) are correlated with poor patient outcome. We have designed and tested both
in vitro
and
in vivo
, a monoamine oxidase B (MAOB) specific prodrug,
PAM
-OBG, that is converted by glioma MAOB into the MGMT inhibitor O
6
-benzylguanine (O
6
BG) and the DNA crosslinking agent acrolein. In cultured glioma cells, we show that
PAM
-OBG is converted to O
6
BG, inhibiting MGMT and sensitizing cells to DNA alkylating agents such as BCNU, CCNU, and Temozolomide (TMZ). In addition, we demonstrate that the acrolein generated is highly toxic in glioma treated with an inhibitor of Nucleotide Excision Repair (NER). In mouse intracranial models of primary human glioma, we show that
PAM
-OBG increases survival of mice treated with either BCNU or CCNU by a factor of six and that in a chemoradiation model utilizing six rounds of TMZ/2Gy radiation, pre-treatment with
PAM
-OBG more than doubled survival time.
...
PMID:PAM-OBG: A monoamine oxidase B specific prodrug that inhibits MGMT and generates DNA interstrand crosslinks, potentiating temozolomide and chemoradiation therapy in intracranial glioblastoma. 2984 63
