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  • Taken together this study gives first insights

    2021-06-21

    Taken together, this study gives first insights into the complex effect of DNMT inhibition on pattern separation. Acute administration of RG108 enhanced pattern separation performance measured with the OPS task and increased Bdnf1 expression. However, this effect was only acute, and was not present anymore after 48 h. Additionally, this upregulation in Bdnf1 expression was accompanied with increased methylation in specific CpG islands in the promoter of the gene. Further studies are needed to reveal the exact effects on DNA methylation in different Eltrombopag Olamine areas as well as the effect of chronic administration of RG108. Furthermore, future studies should indicate whether pharmacological enhancement of pattern separation performance can help patients suffering from disorders like anxiety or schizophrenia.
    Introduction The methylated DNA bases N4-methylcytosine, N6-methyladenine and C5-methylcytosine are considered additional bases of the genetic code that carry epigenetic information not encoded in the DNA sequence itself (reviewed in Refs. [1] and [2]). Generally, DNA methylation has an important role in protein-DNA interaction by either enhancing or disrupting binding of proteins to DNA. The enzymes responsible for these modifications are DNA methyltransferases (DNA-MTases), which catalyze the transfer of a methyl group from S-adenosyl--methionine (SAM) to the three above-mentioned positions in DNA [3]. In contrast to the role of eukaryotic DNA-MTases, most prokaryotic DNA-MTases are members of a host protection system, the restriction-modification (RM) system [4,5]. The main function of DNA-MTases in the RM system is methylation of host DNA which confers protection from digestion by restriction endonucleases (REases) that recognize the same specific DNA sequence [6]. Some DNA-MTases are not accompanied by an REase and are so-called orphan MTases [7]. The roles of orphan MTases have been proposed to be within gene regulation, DNA replication, cell cycle and directing post-replicative mismatch repair on newly synthesized DNA strands by de novo methylation [2,[8], [9], [10], [11], [12]]. In contrast to eukaryotic DNA 5-cytosine methyltransferases (C5-DNA-MTases), being multi-domain proteins and complexes, the prokaryotic enzymes are single-domain proteins [13]. When three-dimensional structures of C5-DNA-MTases are compared, both prokaryotic and eukaryotic catalytic DNA-MTase domains are similar in structural organization. The catalytic domains are organized into a large and a small sub-domain separated by a marked cleft [14]. Despite their structural homology, the sequence similarity among C5-DNA-MTases is low with the exception of ten conserved motifs, named with roman numerals I-X [3]. In addition to these motifs, all C5-DNA-MTases possess a variable region; the Target Recognition Domain (TRD), which is involved in sequence recognition [3,9]. Most of the conserved motifs are located in the large sub-domain, while the TRD comprises most of the small sub-domain. The best conserved motifs (I, IV, VI, VIII, IX and X) are either structural (motif IX), or involved in SAM binding (motifs I and X), DNA binding (motifs VI, VIII and TRD) or catalysis (motif IV) [3,[14], [15], [16]]. Psychrobacter arcticus 273–4 is a gram-negative bacterium discovered in 20–30 thousand year old permafrost soil in Kolyma, Siberia [17]. P. arcticus 273-4 has been genome sequenced [18], grows at temperatures from −10 to 28 °C and has generation time of 3.5 days at temperatures below zero [[17], [18], [19], [20]]. At the protein level, P. arcticus 273–4 possesses many common features for psychrophilic bacteria, such as reduced use of proline, arginine and acidic amino acids, an increased lysine content, as well as encoding several cold shock proteins [[18], [19], [20], [21]]. In the present study, a C5-DNA-MTase from P. arcticus 273–4, ParI, was characterized on the basis of its potential to possess features relevant for biotechnological applications, such as labeling of biopolymers, DNA mapping or epigenetic analysis [[22], [23], [24]].