Highlights d Discovery of JH-RE-06, a compound disrupting REV1-POL zmediated mutagenic TLS d JH-RE-06 induces REV1 dimerization to block the REV1-REV7 interaction d JH-RE-06 sensitizes tumors to cisplatin and reduces mutagenesis in vitro d JH-RE-06 suppresses tumor progression in mice and prolongs animal survival

The AlkB protein is a repair enzyme that uses an α-ketoglutarate/Fe(II)-dependent mechanism to repair alkyl DNA adducts. AlkB has been reported to repair highly susceptible substrates, such as 1-methyladenine and 3-methylcytosine, more efficiently in ss-DNA than in ds-DNA. Here, we tested the repair of weaker AlkB substrates 1-methylguanine and 3-methylthymine, and found that AlkB prefers to repair them in ds-DNA. We also discovered AlkB and its human homologs, ABH2 and ABH3, are able to repair the aforementioned adducts when the adduct is present in a mismatched base pair. These observations demonstrate the strong adaptability of AlkB on repairing various adducts in different environments.

Fusarium head blight (FHB) mainly caused by F. graminearum, always brings serious damage to wheat production worldwide. In this study, we found that strain LM2303 had strong antagonist activity against F. graminearum and significantly reduced disease severity of FHB with the control efficiency of 72.3% under field conditions. To gain a comprehensive understanding of the biocontrol potential of strain LM2303 against FHB, an integrated approach of genome mining and chemical analysis was employed. The whole genome of strain LM2303 was obtained and analyzed, showing the largest number of genes/gene clusters associated with biocontrol functions as compared with the known biocontrol strains (FZB42, M75, CAU B946). And strain LM2303 was accurately determined as a member of the B. velezensis clade using the phylogenomic analysis of single-copy core genes. Through genome mining, 13 biosynthetic gene clusters(BGCs) encoding secondary metabolites with biocontrol functions were identified, which were further confirmed through chemical analyses such as UHPLC-ESI-MS, including three antifungal metabolites (fengycin B, iturin A, and surfactin A), eight antibacterial metabolites (surfactin A, butirosin, plantazolicin and hydrolyzed plantazolicin, kijanimicin, bacilysin, difficidin, bacillaene A and bacillaene B, 7-o-malonyl macrolactin A and 7-o-succinyl macrolactin A), the siderophore bacillibactin, molybdenum cofactor and teichuronic acid. In addition, genes/gene clusters involved in plant colonization, plant growth promotion and induced systemic resistance were also found and analyzed, along with the corresponding metabolites. Finally, four different mechanisms of strain LM2303 involved in the biocontrol of FHB were putatively obtained. This work provides better insights into a mechanistic understanding of strain LM2303 in control of FHB, reinforcing the higher potential of this strain as a powerful biocontrol strain agent (BCA) for FHB control. The results also provide scientific reference and comparison for other biocontrol strains.

Cancer-associated mutations often lead to perturbed cellular energy metabolism and accumulation of potentially harmful oncometabolites. One example is the chiral molecule 2-hydroxyglutarate (2HG); its two stereoisomers (D- and L-2HG) have been found with abnormally high concentrations in tumors featuring anomalous metabolic pathways. 2HG has been demonstrated to competitively inhibit several α-ketoglutarate (αKG)- and non-heme iron-dependent dioxygenases, including some of the AlkB family DNA repair enzymes, such as ALKBH2 and ALKBH3. However, previous studies have only provided the IC50 values of D-2HG on the enzymes and the results have not been correlated to physiologically relevant concentrations of 2HG and αKG in cancer cells. In this work, we carried out detailed kinetic analyses of DNA repair reactions catalyzed by ALKBH2, ALKBH3 and the bacterial AlkB in the presence of D- and L-2HG in both double and single stranded DNA contexts. We determined kinetic parameters of inhibition, including kcat, KM, and Ki. We also correlated the relative concentrations of 2HG and αKG previously measured in tumor cells with the inhibitory effect of 2HG on the AlkB family enzymes. Both D- and L-2HG significantly inhibited the human DNA repair enzymes ALKBH2 and ALKBH3 under pathologically relevant concentrations (73–88% for D-2HG and 31–58% for L-2HG inhibition). This work provides a new perspective that the elevation of either D- or L-2HG in cancer cells may contribute to an increased mutation rate by inhibiting the DNA repair carried out by the AlkB family enzymes and thus exacerbate the genesis and progression of tumors.

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Deoxynivalenol (DON) is the secondary metabolite of Fusarium graminearum, which is always found in Fusarium head blight of wheat. In this study, gaseous ozone was used to treat both DON solution and scabbed wheat to investigate the effectiveness of ozone treatment on DON degradation and the effect of ozone on the quality parameters of wheat. It was found that gaseous ozone had a significant effect on DON reduction in solution, when 10 mg l(-1) gaseous ozone was used to treat a 1 μg ml(-1) of DON solution, the degradation rate of DON was 93.6% within 30 s. Lower initial concentrations of DON solution treated with higher concentrations of ozone, and longer times showed higher DON degradation rates. Gaseous ozone was effective against DON in scabbed wheat. The degradation rate of DON increased with ozone concentration and processing time. The correlation between the time and degradation rate was y = -1.1926x(2) + 11.427x - 8.7787. In the process of ozone oxidation, a higher moisture content of wheat was more sensitive than that of lower moisture content to ozone under the same conditions. All samples were treated with different concentrations of ozone for 4 h to investigate the effect of ozone on wheat quality. No significant detrimental changes in the starch pasting properties of wheat were observed after all the samples were treated with ozone within 4 h. On the other hand, there was a slight rise in the dough development time and stability time, which meant the quality of flour improved after ozone treatment.

5-Methylcytosine (5mC) in DNA CpG islands is an important epigenetic biomarker for mammalian gene regulation. It is oxidized to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) by the ten-eleven translocation (TET) family enzymes, which are α-ketoglutarate (α-KG)/Fe(II)-dependent dioxygenases. In this work, we demonstrate that the epigenetic marker 5mC is modified to 5hmC, 5fC, and 5caC in vitro by another class of α-KG/Fe(II)-dependent proteins—the DNA repair enzymes in the AlkB family, which include ALKBH2, ALKBH3 in huamn and AlkB in Escherichia coli . Theoretical calculations indicate that these enzymes may bind 5mC in the syn -conformation, placing the methyl group comparable to 3-methylcytosine, the prototypic substrate of AlkB. This is the first demonstration of the AlkB proteins to oxidize a methyl group attached to carbon, instead of nitrogen, on a DNA base. These observations suggest a broader role in epigenetics for these DNA repair proteins.

Aims This study aimed to obtain an antagonistic endophyte against Sclerotium rolfsii from peanut seeds, evaluate the biocontrol efficacy towards peanut stem rot and explore its antifungal mechanism against S. rolfsii. Methods and Results Thirty‐seven endophytic bacteria were isolated from peanut seeds, six of which exhibited stronger antagonistic activities against S. rolfsii (inhibition rate, IR of hyphae growth ≥70%). Strain LHSB1, the strongest antagonistic strain, was identified as Bacillus velezensis. LHSB1 showed 93·8% of radial growth inhibition of S. rolfsii hyphae and exhibited obvious antagonistic activity against another six pathogenic fungi of peanut. Pot experiments showed two different LHSB1 treatments both significantly reduced the disease incidence and severity of stem rot (P < 0·05) compared to the controls, and the biocontrol efficacy reached 62·6–70·8%, significantly higher than that of Carbendazim control (P < 0·05). Further analyses revealed LHSB1 culture filtrate significantly inhibited sclerotia formation and germination, caused the abnormalities and membrane integrity damage of S. rolfsii hyphae, which might be the possible mode of action of LHSB1 against S. rolfsii. Three antifungal lipopeptides bacillomycin A, surfactin A and fengycin A, were detected in LHSB1 culture extracts by UPLC‐ESI‐MS, which could be responsible for the biocontrol activity of LHSB1 against S. rolfsii. Conclusion Our results suggested that the seed‐borne endophytic B. velezensis LHSB1 would be a tremendous potential agent for the biocontrol of peanut stem rot caused by S. rolfsii. Significance and Impact of the Study This comprehensive study provides a candidate endophytic biocontrol strain and reveals its antifungal mechanism against S. rolfsi. To the best of our knowledge, this is the first time that seed‐borne endophytic B. velezensis was used as the biocontrol agent to control peanut stem rot.