Nickel-Catalyzed Enantioselective Synthesis of Dienyl Sulfoxide.

Sulfoxides are widely used in the pharmaceutical industry and as ligands in asymmetric catalysis. However, the efficient asymmetric synthesis of this structural motif remains limited. In this study, we disclosed a Ni-catalyzed enantioconvergent reaction that utilizes both racemic allenyl carbonates and ß-sulfinyl esters. Our method employs cheap and more sustainable Ni(II) as a precatalyst and successfully overcomes the challenging poisoning effect and instability of sulfenate generated in situ. This enables the synthesis of a series of dienyl sulfoxides with enantioselectivity of up to 98 % ee. The product exhibits tremendous potential in various applications, including diastereoselective Diels-Alder reactions, coordination with transition metals, and incorporation into medicinal compounds, among others. Using a combination of experimental and computational methods, we have uncovered an interesting associated outersphere mechanism that contrasts with conventional mechanisms commonly observed in asymmetric transition metal catalysis.

FAM122A maintains DNA stability possibly through the regulation of topoisomerase IIα expression.

FAM122A is a housekeeping gene and highly conserved in mammals. More recently, we have demonstrated that FAM122A is essential for maintaining the growth of hepatocellular carcinoma cells, in which we unexpectedly found that FAM122A deletion increases γH2AX protein level, suggesting that FAM122A may participate in the regulation of DNA homeostasis or stability. In this study, we continued to investigate the potential role of FAM122A in DNA damage and/or repair. We found that CRISPR/Cas9-mediated FAM122A deletion enhances endogenous DNA damages in cancer cells but not in normal cells, demonstrating a significant increase in γH2AX protein and foci formation of γH2AX and 53BP1, as well as DNA breaks by comet assay. Further, we found that FAM122A deletion greatly increases TOP2α protein level, and significantly and specifically enhances TOP2 poisons (etoposide and doxorubicin)-induced DNA damage effects in cancer cells. Moreover, FAM122A is found to be interacted with TOP2α, instead of TOP2ß. However, FAM122A knockout doesn't affect the intracellular ROS levels and the process of DNA repair after removal of etoposide with short-term stimulation, suggesting that FAM122A deletion-enhanced DNA damage does not result from endogenous overproduction of ROS and/or impairment of DNA repair ability. Collectively, our study provides the first demonstration that FAM122A is critical for maintaining DNA stability probably by modulating TOP2α protein, and FAM122A deletion combined with TOP2-targeted drugs may represent a potential novel chemotherapeutic strategy for cancer patients.

Detection of microRNAs by the combination of Exonuclease-III assisted target recycling amplification and repeated-fishing strategy.

A simple but effective method for the detection of miRNAs was proposed by integrating exonuclease-III assisted target recycling amplification and repeated-fishing strategy. In the proposed method, exonuclease-III assisted target recycling amplification reaction is adopted to produce a large amount of DNA fragments with fluorescence group at its 5' end in the presence of the target miRNA, which are then repeatedly fished out from the reaction mixture by a gold foil modified with a capture probe and transferred into a so-called 'product tube'. The amount of the target miRNA can then be determined from the fluorescence measurement of the solution in the 'product tube'. Application to the detection of miRNA-155 in samples of KH-2 and BRSA-2B cells revealed that the proposed method could achieve sensitive and accurate quantification of the target miRNA with a limit of detection of 36 fM and recovery rates in the range from 96.2% to 105%. Its simplicity, sensitivity and resistance to possible fluorescence interferences in complex biological samples make the proposed method a potentially competitive alternative for miRNAs detection in complex biological samples.

FAM122A Inhibits Erythroid Differentiation through GATA1.

FAM122A is a highly conserved housekeeping gene, but its physiological and pathophysiological roles remain greatly elusive. Based on the fact that FAM122A is highly expressed in human CD71+ early erythroid cells, herein we report that FAM122A is downregulated during erythroid differentiation, while its overexpression significantly inhibits erythrocytic differentiation in primary human hematopoietic progenitor cells and erythroleukemia cells. Mechanistically, FAM122A directly interacts with the C-terminal zinc finger domain of GATA1, a critical transcriptional factor for erythropoiesis, and reduces GATA1 chromatin occupancy on the promoters of its target genes, thus resulting in the decrease of GATA1 transcriptional activity. The public datasets show that FAM122A is abnormally upregulated in patients with ß-thalassemia. Collectively, our results demonstrate that FAM122A plays an inhibitory role in the regulation of erythroid differentiation, and it would be a potentially therapeutic target for GATA1-related dyserythropoiesis or an important regulator for amplifying erythroid cells ex vivo.

FAM122A supports the growth of hepatocellular carcinoma cells and its deletion enhances Doxorubicin-induced cytotoxicity.

FAM122A is a highly conserved protein in mammals, however its function is still largely unknown so far. In this study, we investigated the potential role of FAM122A in hepatocellular carcinoma (HCC). By analyzing HCC patient cohorts from RNA sequencing datasets, we found the expression level of FAM122A mRNA is significantly upregulated in HCC patients. Moreover, this abnormally higher expression pattern of FAM122A protein was also found in partial HCC tumor tissues, compared with the normal parts. Further, we demonstrated that CRISPR/Cas9-mediated FAM122A knockout significantly inhibits the growth, clonogenic potential and xenografts of HCC cells, induces cell cycle arrest and reduces the expression of proliferation-related genes. Interestingly, FAM122A deletion significantly enhances the cytotoxicity effect of Doxorubicin (Dox), a drug used in standard chemotherapy in HCC patients. In contrary, overexpression of FAM122A not only promotes HCC cell growth, but also inhibits Dox-induced DNA damage and cell death. Considering that FAM122A is previously identified as an endogenous inhibitor of PP2A, we asked whether FAM122A regulating HCC cell growth is associated with PP2A. The results showed FAM122A can also modulate PP2A activity in HCC cells although the modulated effect is relatively slight, however, treatment with a PP2A inhibitor okadaic acid did not rescue the inhibitory effects of cell growth and proliferation in FAM122A deletion cells, indicating that FAM122A may support HCC cell growth independent of its ability to modulate PP2A. Collectively, these results suggest that FAM122A is required for maintaining HCC cell growth, and its elimination combined with chemotherapy may represent a potential novel therapeutic strategy for HCC patients.