DDX11 was recently identified as a cause of Warsaw breakage syndrome (WABS). However, the functional mechanism of DDX11 and the contribution of clinically described mutations to the pathogenesis of WABS are elusive. Here, we show that DDX11 is a novel nucleolar protein that preferentially binds to hypomethylated active ribosomal DNA (rDNA) gene loci, where it interacts with upstream binding factor (UBF) and the RNA polymerase I (Pol I). DDX11 knockdown changed the epigenetic state of rDNA loci from euchromatic structures to more heterochromatic structures, reduced the activity of UBF, decreased the recruitment of UBF and RPA194 (a subunit of Pol I) to rDNA promoter, suppressed rRNA transcription and thereby inhibited growth and proliferation of HeLa cells. Importantly, two indentified WABS-derived mutants, R263Q and K897del, and a Fe-S deletion construct demonstrated significantly reduced binding abilities to rDNA promoters and lowered DNA-dependent ATPase activities compared with wild-type DDX11. Knockdown of the zebrafish ortholog of human DDX11 by morpholinos resulted in growth retardation and vertebral and craniofacial malformations in zebrafish, concomitant with the changes in histone epigenetic modifications at rDNA loci, the reduction of Pol I recruitment to the rDNA promoter and a significant decrease in nascent pre-RNA levels. These growth disruptions in zebrafish in response to DDX11 reduction showed similarities to the clinically described developmental abnormalities found in WABS patients for the first time in any vertebrate. Thus, our results indicate that DDX11 functions as a positive regulator of rRNA transcription and provides a novel insight into the pathogenesis of WABS.
A novel 2-oxazoline-benzoxazine compound (POB) was synthesized and characterized by FT-IR, 1 H-NMR, 13 C-NMR and MS. Simultaneously, octa(aminophenyl)silsesquioxane was also synthesized and incorporated in POB to prepare the nanocomposites. The 1 H-NMR spectra of the formulated POB and OAPS solution showed the reaction of 2-oxazoline ring and amino group at room temperature, the reaction mechanism was suggested for the first time, and finally the product containing benzamidine structure was obtained. DMA results showed that little content of OAPS (0.5 wt%) remarkably enhanced the thermal properties of PolyPOB; however, excessive content of OAPS may be impair the thermal properties of the nanocomposite. It is speculated that the introduced OAPS decreased the packing density of PolyPOB, which led to the decreasing of char yield (at 800 • C) with the increasing of OAPS contents. The TEM micrographs indicated that 0.5 wt% content of OAPS dispersed homogenously in PolyPOB matrix, while aggregation will occur in the nanocomposites containing 5 wt% OAPS.
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