ZNF830 mediates cancer chemoresistance through promoting homologous-recombination repair.

Homologous recombination (HR), which mediates the repair of DNA double-strand breaks (DSB), is crucial for maintaining genomic integrity and enhancing survival in response to chemotherapy and radiotherapy in human cancers. However, the mechanisms of HR repair in treatment resistance for the improvement of cancer therapy remains unclear. Here, we report that the zinc finger protein 830 (ZNF830) promotes HR repair and the survival of cancer cells in response to DNA damage. Mechanistically, ZNF830 directly participates in DNA end resection via interacting with CtIP and regulating CtIP recruitment to DNA damage sites. Moreover, the recruitment of ZNF830 at DNA damage sites is dependent on its phosphorylation at serine 362 by ATR. ZNF830 directly and preferentially binds to double-strand DNA with its 3' or 5' overhang through the Zinc finger (Znf) domain, facilitating HR repair and maintaining genome stability. Thus, our study identified a novel function of ZNF830 as a HR repair regulator in DNA end resection, conferring the chemoresistance to genotoxic therapy for cancers those that overexpress ZNF830.

Targeting miR-21 with Sophocarpine Inhibits Tumor Progression and Reverses Epithelial-Mesenchymal Transition in Head and Neck Cancer.

A major challenge for cancer chemotherapy is the development of safe and clinically effective chemotherapeutic agents. With its low toxicity profile, sophocarpine (SC), a naturally occurring tetracyclic quinolizidine alkaloid derived from Sophora alopecuroides L, has shown promising therapeutic properties, including anti-inflammatory, anti-nociceptive, and antivirus activities. However, the antitumor efficacy of SC and its underlying mechanisms have not been completely delineated. In the present study, the inhibitory effect of SC on head and neck squamous cell carcinoma (HNSCC) progression and possible mechanisms for this effect involving microRNA-21 (miR-21) regulation were investigated. By cell viability, Transwell, and wound healing assays, we show that SC effectively inhibited proliferation, invasion, and migration of HNSCC cells. Moreover, SC exerted its growth-inhibitory effect via the downregulation of miR-21 expression by blocking Dicer-mediated miR-21 maturation. Furthermore, SC treatment led to the increased expression of PTEN and p38MAPK phosphorylation as well as the reversal of epithelial-mesenchymal transition (EMT), which was rescued by ectopic expression of miR-21 in cells. Notably, SC dramatically repressed tumor growth without observable tissue cytotoxicity in a mouse xenograft model of HNSCC. Our findings offer a preclinical proof of concept for SC as a leading natural agent for HNSCC cancer therapy.

Genetic analysis of phytoene synthase 1 (Psy1) gene function and regulation in common wheat.

BACKGROUND: Phytoene synthase 1 (PSY1) is the most important regulatory enzyme in carotenoid biosynthesis, whereas its function is hardly known in common wheat. The aims of the present study were to investigate Psy1 function and genetic regulation using reverse genetics approaches. RESULTS: Transcript levels of Psy1 in RNAi transgenic lines were decreased by 54-76 % and yellow pigment content (YPC) was reduced by 26-35 % compared with controls, confirming the impact of Psy1 on carotenoid accumulation. A series of candidate genes involved in secondary metabolic pathways and core metabolic processes responded to Psy1 down-regulation. The aspartate rich domain (DXXXD) was important for PSY1 function, and conserved nucleotides adjacent to the domain influenced YPC by regulating gene expression, enzyme activity or alternative splicing. Compensatory responses analysis indicated that three Psy1 homoeologs may be coordinately regulated under normal conditions, but separately regulated under stress. The period 14 days post anthesis (DPA) was found to be a key regulation node during grain development. CONCLUSION: The findings define key aspects of flour color regulation in wheat and facilitate the genetic improvement of wheat quality targeting color/nutritional specifications required for specific end products.

Transcutaneous Electrical Acupuncture Point Stimulation Is Cardioprotective for Patients With Stable Ischemic Heart Disease.

We evaluated the effects of electroacupuncture (EA) at Neiguan and Ximen on the prognosis of patients with stable ischemic heart disease. A total of 240 patients symptomatic with suspected coronary artery disease referred for coronary angiography were analyzed, and 232 patients (62.3 ± 9.1 years) with stable ischemic heart disease were included. The primary end point was major adverse cardiovascular events (MACEs), defined as a composite of recurrent angina requiring hospitalization, nonfatal acute myocardial infarction, cardiogenic death, and death from any other causes. Over a mean follow-up of 12 months, 9 patients (8.4%) in the EA treatment group and 22 patients (19.3%) in the control group occurred. Patients treated with EA had a significantly smaller risk of MACE (p = 0.021), recurrence of unstable angina (p = 0.033), and nonfatal myocardial infraction (p = 0.038) than that of those treated without EA. Kaplan-Meier analysis revealed that the EA and control groups began to separate at approximately 5 months and continued to diverge up to study termination. Moreover, multivariate Cox analysis showed that treatment with EA was associated with decreased likelihood of MACE within 12 months of follow-up. The circulating levels of cluster of differentiation 40 ligand but hypersensitive C-reactive protein were lower (166.0 ± 92.6 pg/ml vs 197.3 ± 79.2 pg/ml, p = 0.012) in the EA group than in the control group and decreased significantly (-30.6 ± 47.2 pg/ml vs -1.1 ± 50.4 pg/ml, p <0.001) after 12 months of treatment. EA is an effective treatment method for supporting patients with stable ischemic heart disease.

Alternative splicing in the coding region of Ppo-A1 directly influences the polyphenol oxidase activity in common wheat (Triticum aestivum L.).

Polyphenol oxidase (PPO) plays a crucial role in browning reactions in fresh and processed fruits and vegetables, as well as products made from cereal grains. Common wheat (Triticum aestivum L.) has a large genome, representing an interesting system to advance our understanding of plant PPO gene expression, regulation and function. In the present study, we characterized the expression of Ppo-A1, a major PPO gene located on wheat chromosome 2A, using DNA sequencing, semi-quantitative RT-PCR, PPO activity assays and whole-grain staining methods during grain development. The results indicated that the expression of the Ppo-A1b allele was regulated by alternative splicing of pre-mRNAs, resulting from a 191-bp insertion in intron 1 and one C/G SNP in exon 2. Eight mRNA isoforms were identified in developing grains based on alignments between cDNA and genomic DNA sequences. Only the constitutively spliced isoform b encodes a putative full-length PPO protein based on its coding sequence whereas the other seven spliced isoforms, a, c, d, e, f, g and h, have premature termination codons resulting in potential nonsense-mediated mRNA decay. The differences in expression of Ppo-A1a and Ppo-A1b were confirmed by PPO activity assays and whole grain staining, providing direct evidence for the influence of alternative splicing in the coding region of Ppo-A1 on polyphenol oxidase activity in common wheat grains.

Acetylation regulates ribonucleotide reductase activity and cancer cell growth.

Ribonucleotide reductase (RNR) catalyzes the de novo synthesis of deoxyribonucleoside diphosphates (dNDPs) to provide dNTP precursors for DNA synthesis. Here, we report that acetylation and deacetylation of the RRM2 subunit of RNR acts as a molecular switch that impacts RNR activity, dNTP synthesis, and DNA replication fork progression. Acetylation of RRM2 at K95 abrogates RNR activity by disrupting its homodimer assembly. RRM2 is directly acetylated by KAT7, and deacetylated by Sirt2, respectively. Sirt2, which level peak in S phase, sustains RNR activity at or above a threshold level required for dNTPs synthesis. We also find that radiation or camptothecin-induced DNA damage promotes RRM2 deacetylation by enhancing Sirt2-RRM2 interaction. Acetylation of RRM2 at K95 results in the reduction of the dNTP pool, DNA replication fork stalling, and the suppression of tumor cell growth in vitro and in vivo. This study therefore identifies acetylation as a regulatory mechanism governing RNR activity.

Nα-acetylated Sir3 stabilizes the conformation of a nucleosome-binding loop in the BAH domain.

In Saccharomyces cerevisiae, acetylation of the Sir3 N terminus is important for transcriptional silencing. This covalent modification promotes the binding of the Sir3 BAH domain to the nucleosome, but a mechanistic understanding of this phenomenon is lacking. By X-ray crystallography, we show here that the acetylated N terminus of Sir3 does not interact with the nucleosome directly. Instead, it stabilizes a nucleosome-binding loop in the BAH domain.