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PARP1 is a DNA-dependent ADP-Ribose transferase with ADP-ribosylation activity that is triggered by DNA breaks and non-B DNA structures to mediate their resolution. PARP1 was also recently identified as a component of the R-loop-associated protein-protein interaction network, suggesting a potential role for PARP1 in resolving this structure. R-loops are three-stranded nucleic acid structures that consist of a RNA–DNA hybrid and a displaced non-template DNA strand. R-loops are involved in crucial physiological processes but can also be a source of genome instability if persistently unresolved. In this study, we demonstrate that PARP1 binds R-loops in vitro and associates with R-loop formation sites in cells which activates its ADP-ribosylation activity. Conversely, PARP1 inhibition or genetic depletion causes an accumulation of unresolved R-loops which promotes genomic instability. Our study reveals that PARP1 is a novel sensor for R-loops and highlights that PARP1 is a suppressor of R-loop-associated genomic instability.

Paramignya trimera (Oliv.) Guillaum (Xao tam phan), found mostly in South Vietnam, is a herbal medicine traditionally used for liver protection ability and dermatologic diseases. Recent studies showed that different extracts, fractions and isolated compounds from P. trimera exhibited many interesting bioactivities such as antioxidant, anticancer, anti-inflammatory and alpha-glucosidase inhibitory activities. However, research on the chemical profile and bioactivities of essential oil from the peels of this species has been limited. Therefore, this study aims to determine the chemical composition of this product and examine its anticancer and antibacterial activities. Phytochemical profile of the essential oil was analyzed using gas chromatography coupled to mass spectrometry. Indeed, twenty-four constituents were characterized; of which sesquiterpenes dominated the profile, with three major compounds: β-caryophyllene (19.09%), α-humulene (24.81%), and trans-muurola-4(14),5-diene (24.84%). P. trimera peel essential oil also contained potent inhibitory effects against six clinical multidrug-resistant bacterial strains including both Gram-positive and Gram-negative bacteria. This extract showed the strongest activity against two Pseudomonas aeruginosa strains with minimum inhibitory concentration (MIC) of 256 µg/mL for both, followed by 2 strains of Staphylococcus aureus and 2 strains of Salmonella sp. with MIC values of 384, 480 and 512 µg/mL, respectively. In addition, P. trimera peel essential oil displayed strong cytotoxicity in a dose-dependent manner against liver HepG2 cancer cells, with the half maximal inhibitory concentration of 21 µg/mL. This preliminary result suggested the potential bioactivities of P. trimera peel essential oil and can be helpful for further investigation to develop an phytomedicine-based therapy for cancer and infectious diseases.

Drawing upon the resource-based and dynamic capability views (RBV and DCV, respectively), this study examines the underlying theoretical mechanism between resource-based management initiatives (RBMI) and the resilience and innovation of Vietnamese small- and medium-sized enterprises (SMEs), taking account of potential boundary conditions. Using time-lag data (three waves of data collection) from 188 SMEs, the study finds that RBMI are positively associated with organizational resilience, which in turn enhances innovation. Our results also indicate that organizational learning mediates the RBMI-organizational resilience/innovation relationships. Finally, self‐awareness of environmental dynamism significantly strengthens the relationships between organizational learning and resilience/innovation. This study is among the first to combine and incorporate the RBV and DCV as a theoretical insight to explain how organizations develop their internal resources as a capacity for resilience and innovation in the emerging market context of Vietnamese SMEs. This study makes both theoretical and contextual contributions.

Lignocellulases are the most important enzymes for bioeconomy development and have gained many interests in mining new coding-genes from metagenomic DNA data recently. However, the identification of genes suitable for successful expression in E. coli for the enzyme characterization is still a big challenge. In this study, 18 lignocellullase genes from metagenomic data of bacteria in goats' rumen, termite gut and humus were expressed in E. coli. Then 18 nucleotide and amino acid sequences were used to measure 12 impact features and to investigate tools for prediction of their E. coli expressibility. The features closely related to the enzymes expression level included aliphatic side chains of amino acids (aliphatic index: AI), grand average of hydropathicity, protein folding ability (fold index: FI) and FI was the most important factor. The investigation of two models for prediction of the enzymes expressibility in E. coli showed that 100% sequences predicted to be high expressibility by Periscope were the sequences expressed at high level in experiments. In contrast, 100% sequences predicted to be low expressibilty by ESPRESSO constituted a low expression level in experiments. This result can be a good reference for screening genes before expressing in E. coli.

Immunofluorescence staining of gH2AX DNA damage marker in human CD34+ hematopoietic progenitor cells.

Heterozygous somatic mutations in spliceosome genes (U2AF1, SF3B1, ZRSR2, or SRSF2) occur in >50% of patients with myelodysplastic syndrome (MDS). These mutations occur early in disease development, suggesting that they contribute to MDS pathogenesis and may represent a unique genetic vulnerability for targeted therapy. Here, we show that RNA splicing perturbation by expression of the U2AF1(S34F) mutant causes accumulation of R loops, a transcription intermediate containing RNA:DNA hybrids and displaced single-stranded DNA, and elicits an ATR response. ATR inhibitors (ATRi) induced DNA damage and cell death in U2AF1(S34F)-expressing cells, and these effects of ATRi were enhanced by splicing modulating compounds. Moreover, ATRi-induced DNA damage was suppressed by overexpression of RNaseH1, an enzyme that specifically removes the RNA in RNA:DNA hybrids, suggesting that the ATRi sensitivity of U2AF1(S34F)-expressing cells arises from R loops. Taken together, our results demonstrate that ATR may represent a novel therapeutic target in patients with MDS carrying the U2AF1(S34F) mutation and potentially other malignancies harboring spliceosome mutations.Significance: This study provides preclinical evidence that patients with MDS or other myeloid malignancies driven by spliceosome mutations may benefit from ATR inhibition to exploit the R loop–associated vulnerability induced by perturbations in splicing. Cancer Res; 78(18); 5363–74. ©2018 AACR.

List of primers used for RNA splicing assay

A new phenylethyl glycoside (1), (S)-1-phenylethyl-6-α-L-arabinopyranosyl-β-D-glucopyranoside), and a new dibenzocyclooctadiene lignan (7), Kasuracin A, together with seven known compounds, were isolated and identified from the leaves of Kadsura coccinea. Their structures were determined by analysis of multinuclear and multidimensional nuclear magnetic resonance (NMR), circular dichroism (CD), mass spectrometry, hydrolysis analysis, or comparison to those reported in the literature. Then, all the isolates 1‒9 were evaluated for their inhibitory effects against nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Among them, compounds 2 and 3 were isolated for the first time from this plant and compounds 3, 7, 8, and 9 significantly inhibited NO production with IC50 values of 36.4, 10.2, 12.3, and 21.7 μM, respectively.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent lung carcinogen present in tobacco products, and exposure to it is likely one of the factors contributing to the development of lung cancer in cigarette smokers. To exert its carcinogenic effects, NNK must be metabolically activated into highly reactive species generating a wide spectrum of DNA damage. We have identified a new class of DNA adducts, DNA-RNA cross-links found for the first time in NNK-treated mice lung DNA using our improved high-resolution accurate mass segmented full scan data-dependent neutral loss MS