Disease relevance of NSC 70896

• Alkylation damage in DNA is repaired by at least three different mechanisms, including damage reversal by oxidative demethylation of 1-methyladenine and 3-methylcytosine by Escherichia coli AlkB [1].
• These results indicate that the 1-methyladenine deficiency in adenocarcinoma 13762 results in the appearance of selected populations of tRNA which are substrates in vitro for adenine-1 methyltransferase [2].
• Pertussis toxin inhibits 1-methyladenine-induced maturation in starfish oocytes [3].

High impact information on NSC 70896

• In starfish oocytes, the hormone 1-methyladenine triggers synchronous meiotic divisions that are accompanied by a rapid 30-fold stimulation of H1K activity [4].
• Here we show that AlkB from Escherichia coli is indeed a 2-oxoglutarate-dependent and iron-dependent DNA repair enzyme that releases replication blocks in alkylated DNA by a mechanism involving oxidative demethylation of 1-methyladenine residues [5].
• Two human homologs of the Escherichia coli AlkB protein, denoted hABH2 and hABH3, were recently shown to directly reverse 1-methyladenine (1meA) and 3-methylcytosine (3meC) damages in DNA [6].
• Furthermore, embryonal fibroblasts from mABH2-deficient mice are unable to remove methyl methane sulfate (MMS)-induced 1meA from genomic DNA and display increased cytotoxicity after MMS exposure [6].
• However, in the absence of any exogenous exposure to methylating agents, mice lacking mABH2, but not mABH3 defective mice, accumulate significant levels of 1meA in the genome, suggesting the presence of a biologically relevant endogenous source of methylating agent [6].

Chemical compound and disease context of NSC 70896

• Mutagenesis, genotoxicity, and repair of 1-methyladenine, 3-alkylcytosines, 1-methylguanine, and 3-methylthymine in alkB Escherichia coli [7].

Biological context of NSC 70896

• Meiosis is re-initiated in starfish oocytes by the action of the hormone 1-methyladenine (1-MA) [8].
• Immediately after spawning into seawater, activation of Na+/H+ antiporters via a heterotrimeric G protein coupling to a 1-methyladenine receptor in the oocyte leads to an intracellular pH increase that can overcome the MI arrest even in the presence of active MAP kinase [9].
• (8R)-HETE, but not (8S)-HETE, triggers the typical decrease in cyclic AMP concentration induced by 1-methyladenine and the burst of protein phosphorylation associated with maturation [10].
• In the starfish ovary, maturing oocytes stimulated by 1-methyladenine undergo synchronous germinal vesicle breakdown and then arrest in metaphase of the first meiotic division (metaphase I) [11].
• Reverse transcription is slowed down and its fidelity suspended by the 1-methyladenine in oligo(A)-tRNAPhe(yeast) [12].

Anatomical context of NSC 70896

• The specificity of the 1-methyladenine receptors, which are localized on the cell membrane of starfish oocytes, has been investigated in Marthasterias glacialis and Asterias rubens [13].
• Gonad-stimulating substance (GSS) secreted from radial nerves induces meiotic maturation of starfish oocytes by stimulating production of 1-methyladenine (1-MeAde) in ovarian follicle cells [14].
• We then investigated whether calpain, which is activated by the increase in cell Ca(2+), could cleave the same proteins that became degraded under the influence of 1-methyladenine and thus be involved in nuclear membrane breakdown [15].
• 1-Methyladenine-producing cell in starfish testis [16].
• The cortical array of microtubules is present in all oocytes before and for about 30 min after the application of 1-methyladenine, the hormone that induces oocyte maturation [17].

Associations of NSC 70896 with other chemical compounds

• In agreement with these results, we found that in vitro repair of 1meA and 3meC in double-stranded DNA by nuclear extracts depended primarily, if not solely, on mABH2 [6].
• The stimulation of oocyte maturation by 1-methyladenine in starfish, and by a steroid in frogs, has been proposed to involve G-protein-coupled receptors [18].
• Inhibition of subsite-substituted leupeptin analogs, potent trypsin inhibitors, on 1-methyladenine-induced germinal vesicle breakdown was investigated in a starfish, Asterina pectinifera [19].
• In response to the maturation-inducing hormone 1-methyladenine, starfish oocytes acquire increased sensitivity to sperm and inositol trisphosphate (InsP3), stimuli that cause a release of calcium from intracellular stores and a rise in intracellular free calcium [20].
• Although MGBG is required during a slightly longer period than the natural hormone 1-methyladenine (1-MeAde), the maturation kinetics are identical [21].

Gene context of NSC 70896

• Significantly, PRK2 is phosphorylated in vivo in response to 1-methyladenine which precedes MPF activation, making PRK2 a candidate regulator of early signaling events of meiotic maturation [22].
• The Escherichia coli AlkB protein encoded by alkB gene was recently found to repair cytotoxic DNA lesions 1-methyladenine (1-meA) and 3-methylcytosine (3-meC) by using a novel iron-catalysed oxidative demethylation mechanism that protects the cell from the toxic effects of methylating agents [23].
• These results suggest that beta gamma dissociates from alpha-subunit by the stimulation of 1-methyladenine and interacts with a cytoplasmic effector, which results in formation of active cdc2 kinase [24].
• Components of the signaling pathway linking the 1-methyladenine receptor to MPF activation and maturation in starfish oocytes [25].
• In starfish oocytes, the beta gamma subunit of G protein mediates 1-methyladenine stimulation of oocyte maturation [26].

Analytical, diagnostic and therapeutic context of NSC 70896

• In contrast microinjection of Ca2+ buffers inhibits 1-methyladenine-induced meiosis reinitiation [27].
• After 1-methyladenine (1-MeAde) treatment, maturing oocytes were packed in a centrifuge tube to remove jelly and excess medium, and then crushed by centrifugation [28].
• In starfish oocytes a calcium transient can consistently be detected with the dye fura-2 in response to perfusion of threshold levels of 1-methyladenine, the hormone responsible for induction of meiotic maturation [29].
• The dynamics of the cytoplasmic and nuclear Ca2+ pools in starfish oocytes arrested at the prophase of the first meiotic division or after induction of meiosis by 1-methyladenine (1-MA) have been studied by confocal microscopy [30].
• Treatment of starfisch oocytes with maturation inducing hormone, 1-methyladenine, was observed by scanning electron microscopy to induce surface alteration [31].

References