Epigenetic Manipulation Induced Production of Immunosuppressive Chromones and Cytochalasins from the Mangrove Endophytic Fungus Phomopsis asparagi DHS-48.

A mangrove endophytic fungus Phomopsis asparagi DHS-48 was found to be particularly productive with regard to the accumulation of substantial new compounds in our previous study. In order to explore its potential to produce more unobserved secondary metabolites, epigenetic manipulation was used on this fungus to activate cryptic or silent genes by using the histone deacetylase (HDAC) inhibitor sodium butyrate and the DNA methyltransferase (DNMT) inhibitor 5-azacytidine (5-Aza). Based on colony growth, dry biomass, HPLC, and 1H NMR analyses, the fungal chemical diversity profile was significantly changed compared with the control. Two new compounds, named phaseolorin J (1) and phomoparagin D (5), along with three known chromones (2-4) and six known cytochalasins (6-11), were isolated from the culture treated with sodium butyrate. Their structures, including their absolute configurations, were elucidated using a combination of detailed HRESIMS, NMR, and ECD and 13C NMR calculations. The immunosuppressive and cytotoxic activities of all isolated compounds were evaluated. Compounds 1 and 8 moderately inhibited the proliferation of ConA (concanavalin A)-induced T and LPS (lipopolysaccharide)-induced B murine spleen lymphocytes. Compound 5 exhibited significant in vitro cytotoxicity against the tested human cancer cell lines Hela and HepG2, which was comparative to the positive control adriamycin and fluorouracil. Our finding demonstrated that epigenetic manipulation should be an efficient strategy for the induction of new metabolites from mangrove endophytic fungi.

Cytospyrone and Cytospomarin: Two New Polyketides Isolated from Mangrove Endophytic Fungus, Cytospora sp.

Two new polyketides, cytospyrone (1), cytospomarin (2), together with three known metabolites dimethoxyphtalide (3), integracin A (4) and integracin B (5), were isolated from the culture of Cytospora sp. from the Chinese mangrove Ceriops tagal. Their structures were elucidated by extensive spectroscopic analyses and time dependent density functional theory (TDDFT), calculation of electronic circular dichroism (ECD) and optical rotation (OR) data. Compound 2 displayed weak inhibitory activity against Escherichia coli GIM1.201 (minimum inhibitory concentration (MIC) value of 0.35 mM). Compounds 4 and 5 displayed significant cytotoxicity against human cancer cell line HepG2 (IC50 values of 5.98 ± 0.12 µM and 9.97 ± 0.06 µM, respectively), more potent than the positive control 5-fluorouracil (IC50 value of 43.50 ± 3.69 µM).

Cell cycle-dependent control of homologous recombination.

DNA double-strand breaks (DSBs) are among the most deleterious type of DNA lesions threatening genome integrity. Homologous recombination (HR) and non-homologous end joining (NHEJ) are two major pathways to repair DSBs. HR requires a homologous template to direct DNA repair, and is generally recognized as a high-fidelity pathway. In contrast, NHEJ directly seals broken ends, but the repair product is often accompanied by sequence alterations. The choice of repair pathways is strictly controlled by the cell cycle. The occurrence of HR is restricted to late S to G2 phases while NHEJ operates predominantly in G1 phase, although it can act throughout most of the cell cycle. Deregulation of repair pathway choice can result in genotoxic consequences associated with cancers. How the cell cycle regulates the choice of HR and NHEJ has been extensively studied in the past decade. In this review, we will focus on the current progresses on how HR is controlled by the cell cycle in both Saccharomyces cerevisiae and mammals. Particular attention will be given to how cyclin-dependent kinases modulate DSB end resection, DNA damage checkpoint signaling, repair and processing of recombination intermediates. In addition, we will discuss recent findings on how HR is repressed in G1 and M phases by the cell cycle.