PubMed · 11365558
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L Highleyman. 1998. Preveon expanded access program broadened.. https://pubmed.ncbi.nlm.nih.gov/11365558/
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DNA N6-methyladenine (6mA) is a newly recognized transcription-associated epigenetic mark in eukaryotes. While its methylation pathway has been well established, the identity of eukaryotic 6mA demethylase(s) responsible for its removal and dynamic regulation has remained elusive. Here, we identify and characterize DMT3 (TtALKBH5), an AlkB family dioxygenase in Tetrahymena thermophila, as a 6mA demethylase in ciliates and potentially several other unicellular eukaryotes with abundant 6mA and a defined AMT1 methyltransferase (MTase) complex, supported by genetic and molecular evidence. DMT3 acts on both fully and hemimethylated ApT dinucleotides, an activity partially facilitated by a naturally occurring cysteine-to-serine substitution. Genome profiling shows that DMT3 is enriched at transcription start sites (TSSs) of 6mA-enriched genes, complementary to the occupancy pattern of the AMT1 complex, where it selectively removes spurious 6mA deposited by AMT1. Genetic disruption of DMT3-mediated demethylation, either by knockout or catalytic inactivation, leads to aberrant 6mA accumulation at TSS regions, transcriptional dysregulation, altered chromatin accessibility, and impaired initiation of sexual reproduction. Notably, simultaneous removal of DMT3 and AMT1 eliminates these defects, indicating that spurious TSS 6mA underlies transcriptional and developmental impairment.
A strategy coupling high-activity nucleases with dimeric TadA-8e optimizes plant Cas12-based adenine base editors, boosts editing efficiency, and provides precise editors for crop breeding and genomics research.
Threshold collision-induced dissociation of M(+)(adenine) with xenon is studied using guided ion beam mass spectrometry. M(+) includes all 10 first-row transition metal ions: Sc(+), Ti(+), V(+), Cr(+), Mn(+), Fe(+), Co(+), Ni(+), Cu(+), and Zn(+). For the systems involving the late metal ions, Cr(+) through Cu(+), the primary product corresponds to endothermic loss of the intact adenine molecule, whereas for Zn(+), this process occurs but to form Zn + adenine(+). For the complexes to the early metal ions, Sc(+), Ti(+), and V(+), intact ligand loss competes with endothermic elimination of purine and of HCN to form MNH(+) and M(+)(C(4)H(4)N(4)), respectively, as the primary ionic products. For Sc(+), loss of ammonia is also a prominent process at low energies. Several minor channels corresponding to formation of M(+)(C(x)H(x)N(x)), x = 1-3, are also observed for these three systems at elevated energies. The energy-dependent collision-induced dissociation cross sections for M(+)(adenine), where M(+) = V(+) through Zn(+), are modeled to yield thresholds that are directly related to 0 and 298 K bond dissociation energies for M(+)-adenine after accounting for the effects of multiple ion-molecule collisions, kinetic and internal energy distributions of the reactants, and dissociation lifetimes. The measured bond energies are compared to those previously studied for simple nitrogen donor ligands, NH(3) and pyrimidine, and to results for alkali metal cations bound to adenine. Trends in these results and theoretical calculations on Cu(+)(adenine) suggest distinct differences in the binding site propensities of adenine to the alkali vs transition metal ions, a consequence of s-dsigma hybridization on the latter.