CDC73/Parafibromin is a critical component of the Paf1 complex (PAF1C), which is involved in transcriptional elongation and histone modifications. Mutations of the human CDC73/HRPT2 gene are associated with hyperparathyroidism-jaw tumor (HPT-JT) syndrome, an autosomal dominant disorder. CDC73/parafibromin was initially recognized as a tumor suppressor by inhibiting cell proliferation via repression of cyclin D1 and c-myc genes. In recent years, it has also shown oncogenic features by activating the canonical Wnt/β-catenin signal pathway. Here, through limited proteolysis analysis, we demonstrate that the evolutionarily conserved human CDC73 N-terminal 111 residues form a globularly folded domain (hCDC73-NTD). We have determined a crystal structure of hCDC73-NTD at 1.02 Å resolution, which reveals a novel protein fold. CDC73-NTD contains an extended hydrophobic groove on its surface that may be important for its function. Most pathogenic CDC73 missense mutations associated with the HPT-JT syndrome are located in the region encoding CDC73-NTD. Our crystal and biochemical data indicate that most CDC73 missense mutations disrupt the folding of the hydrophobic core of hCDC73-NTD, while others such as the K34Q mutant reduce its thermostability. Overall, our results provide a solid structural basis for understanding the structure and function of CDC73 and its association with the HPT-JT syndrome and other diseases.
Phenol is a ubiquitous pollutant and can contaminate natural water resources. Hence, the removal of phenol from wastewater is of significant importance. A series of biological methods were used to remove phenol based on the natural ability of microorganisms to degrade phenol, but the tolerance mechanism of phenol-degraded strains to phenol are not very clear. Morphological observation on Candida tropicalis showed that phenol caused the reactive oxygen species (ROS) accumulation, damaging the mitochondrial and the endoplasmic reticulum. On the basis of transcriptome data and cell wall susceptibility analysis, it was found that C. tropicalis prevented phenol-caused cell damage through improvement of cell wall resistance, maintenance of high-fidelity DNA replication, intracellular protein homeostasis, organelle integrity, and kept the intracellular phenol concentration at a low level through cell-wall remodeling and removal of excess phenol via MDR/MXR transporters. The knowledge obtained will promote the genetic modification of yeast strains in general to tolerate the high concentrations of phenol and improve their efficiency of phenol degradation.
Elongation-induced leaf emergence is one way for plants to deal with complete submergence by ‘escaping’ from water. This growth strategy is hypothesised to be more beneficial under single long-term submergence than under repeated short-term submergence events (i.e. fluctuating environment), as costs of repeated plant ‘adjustment’ would exceed the initial benefits of shoot elongation. To test this idea, 2-week-old plants of Chloris gayana Kunth. cv. Fine Cut (a submergence-tolerant cultivar first selected by a screening experiment) were grown for 4 weeks under (i) control conditions, (ii) two 1-week submergence cycles, or (iii) one 2-week submergence cycle. Additionally, a set of plants were placed below nettings to assess the cost of remaining forcedly submerged. Impeding leaves emergence through nettings did not compromise survival when submergence was 1-week long, but determined the death of all plants when extended to 2 weeks. Growth as affected by flooding regime revealed that under one 2-week submergence event, plants accumulated a 2.9-fold higher dry mass than when they experienced the same submergence duration in separate events along 1week. The ‘escape’ strategy in the grass C. gayana, by which leaf contact with air is re-established, is essential for its survival, and it is more beneficial for plant growth under long-term submergence than under repeated short-term submergence cycles.
The helicase superfamily 2 (SF2) proteins are involved in essentially every step in DNA and RNA metabolism. The radD (yejH) gene, which belongs to SF2, plays an important role in DNA repair. The RadD protein includes all seven conserved SF2 motifs and has shown ATPase activity. Here, we first reported the structure of RadD from Escherichia coli containing two RecA‐like domains, a zinc finger motif, and a C‐terminal domain. Based on the structure of RadD and other SF2 proteins, we then built a model of the RedD‐ATP complex.
Overuse of β2-adrenoceptor agonist bronchodilators evokes receptor desensitization, decreased efficacy, and an increased risk of death in asthma patients. Bronchodilators that do not target β2-adrenoceptors represent a critical unmet need for asthma management. Here, we characterize the utility of osthole, a coumarin derived from a traditional Chinese medicine, in preclinical models of asthma. In mouse precision-cut lung slices, osthole relaxed preconstricted airways, irrespective of β2-adrenoceptor desensitization. Osthole administered in murine asthma models attenuated airway hyperresponsiveness, a hallmark of asthma. Osthole inhibited phosphodiesterase 4D (PDE4D) activity to amplify autocrine prostaglandin E2 signaling in airway smooth muscle cells that eventually triggered cAMP/PKA-dependent relaxation of airways. The crystal structure of the PDE4D complexed with osthole revealed that osthole bound to the catalytic site to prevent cAMP binding and hydrolysis. Together, our studies elucidate a specific molecular target and mechanism by which osthole induces airway relaxation. Identification of osthole binding sites on PDE4D will guide further development of bronchodilators that are not subject to tachyphylaxis and would thus avoid β2-adrenoceptor agonist resistance.
Cadmium pollution and harmful cyanobacterial blooms are two prominent environmental problems. The interactive effects of cadmium(II) and harmful cyanobacteria on rice seedlings remain unknown. In order to elucidate this issue, the interactive effects of cadmium(II) and Microcystis aeruginosa FACHB905 on the growth and antioxidant responses of rice seedling were investigated in this study, as well as the accumulation of cadmium(II) and microcystins. The results showed that the growth of rice seedlings was inhibited by cadmium(II) stress but promoted by inoculation of M. aeruginosa FACHB905. cadmium(II) stress induced oxidative damage on rice seedlings. Inoculation of M. aeruginosa FACHB905 alleviated the toxicity of cadmium(II) on rice seedlings. The accumulation of cadmium(II) in rice seedlings was decreased by M. aeruginosa FACHB905, but the translocation of cadmium(II) from root to shoot was increased by this cyanobacterium. The accumulation of microcystins in rice seedlings was decreased by cadmium(II). Results presented in this study indicated that cadmium(II) and M. aeruginosa had antagonistic toxicity on rice seedlings. The findings of this study throw new light on evaluation of ecological- and public health-risks for the co-contamination of cadmium(II) and harmful cyanobacteria.
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