Histone H3K9 methylation is required for DNA methylation and silencing of repetitive elements in plants and filamentous fungi. In mammalian cells however, deletion of the H3K9 histone methyltransferases (HMTases) Suv39h1 and Suv39h2 does not affect DNA methylation of the endogenous retrovirus murine leukaemia virus, indicating that H3K9 methylation is dispensable for DNA methylation of retrotransposons, or that a different HMTase is involved. We demonstrate that embryonic stem (ES) cells lacking the H3K9 HMTase G9a show a significant reduction in DNA methylation of retrotransposons, major satellite repeats and densely methylated CpG-rich promoters. Surprisingly, demethylated retrotransposons remain transcriptionally silent in G9a IntroductionRetrotransposons, including long terminal repeat (LTR) and non-LTR elements, are widely dispersed in the euchromatic compartment in higher mammals (Kuff and Lueders, 1988;Medstrand et al, 2002), constituting B37% of the mouse genome (Mouse Genome Sequencing Consortium, 2002). A subset of these elements are transcriptionally competent, placing a significant mutational load on their hosts (Maksakova et al, 2006). To minimize the likelihood of retrotransposition, a number of pathways that function at the transcriptional or post-transcriptional stages of the replicative cycle have evolved to inhibit the expression of these parasitic elements. DNA methylation for example, has an important function in transcriptional silencing of retrotransposons in mammalian cells (Li et al, 1992;Yoder et al, 1997;Walsh et al, 1998), as illustrated by the high level of expression of the intracisternal A particle (IAP) endogenous retrovirus (ERV) in mouse embryos deficient in the DNA methyltransferase (DNMT), Dnmt1 (Walsh et al, 1998). DNA methylation also has a critical function in transcriptional silencing of repetitive elements and their relics in filamentous fungi and plants (Goyon et al, 1996;Lindroth et al, 2001;Zhou et al, 2001), substantiating the importance of this epigenetic mark in suppressing transposable elements in distantly related eukaryotes. Repetitive elements in eukaryotes are also marked by specific covalent histone modifications (Bernstein et al, 2007). Methylation of lysine 9 of the histone H3 tail (H3K9) in particular, has an important function in silencing of these elements in yeast (Nakayama et al, 2001), filamentous fungi (Tamaru and Selker, 2001), plants (Jackson et al, 2002) and animals (Martens et al, 2005). Recent genome-wide studies reveal that ERVs are marked by H3K9 dimethylation (H3K9me2) and/or H3K9 trimethylation (H3K9me3) in murine cells Martens et al, 2005;Mikkelsen et al, 2007); however, the specific histone methyltransferases (HMTases) responsible have not been identified.Intriguingly, the H3K9 HMTase DIM-5 is required for CpG methylation in Neurospora (Tamaru and Selker, 2001) and the H3K9 HMTase KRYPTONITE is required for CpNpG methylation in Arabidopsis (Jackson et al, 2002), suggesting the existence of an evolutionarily conserved silencing pathway in wh...
As a recently discovered DNA repair enzyme, tyrosyl-DNA phosphodiesterase 1 (TDP1) removes topoisomerase IB (TOP1)-mediated DNA protein cross-links. Inhibiting TDP1 can potentiate the cytotoxicity of TOP1 inhibitors and overcome cancer cell resistance to TOP1 inhibitors. On the basis of our previous study, herein we report the synthesis of benzophenanthridinone derivatives as TOP1 and TDP1 inhibitors. Seven compounds (C2, C4, C5, C7, C8, C12, and C14) showed a robust TOP1 inhibitory activity (+++ or ++++), and four compounds (A13, C12, C13, and C26) showed a TDP1 inhibition (half-maximal inhibitory concentration values of 15 or 19 μM). We also show that the dual TOP1 and TDP1 inhibitor C12 induces both cellular TOP1cc, TDP1cc formation and DNA damage, resulting in cancer cell apoptosis at a sub-micromolar concentration. In addition, C12 showed an enhanced activity in drug-resistant MCF-7/TDP1 cancer cells and was synergistic with topotecan in both MCF-7 and MCF-7/TDP1 cells.
The emergence of drug resistance in bacterial pathogens is a growing clinical problem that poses difficult challenges in patient management. To exacerbate this problem, there is currently a serious lack of antibacterial agents that are designed to target extremely drug-resistant bacterial strains. Here we describe the design, synthesis and antibacterial testing of a series of 40 novel indole core derivatives, which are predicated by molecular modeling to be potential glycosyltransferase inhibitors. Twenty of these derivatives were found to show in vitro inhibition of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. Four of these strains showed additional activity against Gram-negative bacteria, including extended-spectrum beta-lactamase producing Enterobacteriaceae, imipenem-resistant Klebsiella pneumoniae and multidrug-resistant Acinetobacter baumanii, and against Mycobacterium tuberculosis H37Ra. These four compounds are candidates for developing into broad-spectrum anti-infective agents.
Tuberculosis (TB) is a chronic, potentially fatal disease caused by Mycobacterium tuberculosis (Mtb). The dihyrofolate reductase in Mtb (mt-DHFR) is believed to be an important drug target in anti-TB drug development. This enzyme contains a glycerol (GOL) binding site, which is assumed to be a useful site to improve the selectivity towards human dihyrofolate reductase (h-DHFR). There have been previous attempts to design drugs targeting the GOL binding site, but the designed compounds contain a hydrophilic group, which may prevent the compounds from crossing the cell wall of Mtb to function at the whole cell level. In the current study, we designed and synthesized a series of mt-DHFR inhibitors that contain a 2,4-diaminopyrimidine core with side chains to occupy the glycerol binding site with proper hydrophilicity for cell entry, and tested their anti-tubercular activity against Mtb H37Ra. Among them, compound 16l showed a good anti-TB activity (MIC = 6.25 μg/mL) with a significant selectivity against vero cells. In the molecular simulations performed to understand the binding poses of the compounds, it was noticed that only side chains of a certain size can occupy the glycerol binding site. In summary, the novel synthesized compounds with appropriate side chains, hydrophobicity and selectivity could be important lead compounds for future optimization towards the development of future anti-TB drugs that can be used as monotherapy or in combination with other anti-TB drugs or antibiotics. These compounds can also provide much information for further studies on mt-DHFR. However, the enzyme target of the compounds still needs to be confirmed by pure mt-DHFR binding assays.
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