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There is evidence that BRCA1, particularly cytoplasmic BRCA1, plays a significant role in initiating apoptosis through various mechanisms. Maintaining the stability of BRCA1 in cancer cells may be a promising therapeutic strategy for breast cancer, especially in cases of triple-negative breast cancer (TNBC) lacking appropriate therapeutic targets. Previously, it was reported that cathepsin S (CTSS) interacts with the BRCT domain of BRCA1, leading to ubiquitin-mediated degradation. We further investigated the critical role of BRCA1 phosphorylation at Ser1387, which is mediated by ionizing radiation (IR)-induced activation of ATM. This phosphorylation event was identified as a key factor in CTSS-mediated ubiquitin degradation of BRCA1. The functional inhibition of CTSS, using small molecules or a knockdown system, sensitized TNBC cells when exposed to IR by restoring the stability of cytoplasmic BRCA1. The increase in cytoplasmic BRCA1 led to the degradation of anti-apoptotic BCL2, which was responsible for the radiosensitization effect observed with CTSS inhibition. These results suggest that inhibiting CTSS may be an effective strategy for radiosensitization in TNBC cells through BCL2 degradation that is mediated by inhibition of CTSS-induced BRCA1 degradation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. TNBC cell lines were exposed to irradiation (10 Gy) after pre-treatment with CTSS inhibitors; RO5461111 (RO) and Z-FL-COCHO (Z-FL). TNBC cell lines with wild-type BRCA1 (WT); MDA-MB-231 (231) & HCC70 and mutant BRCA1 (MT); MDA-MB-436 (436) & HCC1937 (1937). (A) Western blot analysis and the quantification of cleaved-PARP1 induction; (B) Cell death was evaluated with PI staining. Results are the means and SD (*p < 0.05, ANOVA)., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The small presynaptic protein α-synuclein (α-syn) is involved in the etiology of Parkinson's disease owing to its abnormal misfolding. To date, little information is known on the role of DNA nanostructures in the formation of α-syn amyloid fibrils. Here, the effects of DNA tetrahedrons on the formation of α-syn amyloid fibrils were investigated using various biochemical and biophysical methods such as thioflavin T fluorescence assay, atomic force microscopy, light scattering, transmission electron microscopy, and cell-based cytotoxicity assay. It has been shown that DNA tetrahedrons decreased the level of oligomers and increased the level of amyloid fibrils, which corresponded to decreased cellular toxicity. The ability of DNA tetrahedron to facilitate the formation of α-syn amyloid fibrils demonstrated that structured nucleic acids such as DNA tetrahedrons could modulate the process of amyloid fibril formation. Our study suggests that DNA tetrahedrons could be used as an important facilitator toward amyloid fibril formation of α-synuclein, which may be of significance in finding therapeutic approaches to Parkinson's disease and related synucleinopathies., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Deoxyribonucleic acid (DNA) is a versatile material with high applicability and inherent biocompatibility. L-DNA, the perfect mirror form of the naturally occurring D-DNA, has been used in DNA nanotechnology. It has thermodynamically identical properties to D-DNA, is capable of self-assembly and bio-orthogonal base-pairing, and is resistant to nuclease activity. We previously constructed an L-DNA tetrahedron (L-Td) and found that this nanostructure has remarkably higher capacity for cell penetration than its natural counterpart (D-Td). L-Td molecules of two different sizes-one with 17-mer per side (L-Td 17 ) and the other with 30-mer per side (L-Td 30 )-were prepared by assembling four L-DNA strands. In this study, cellular uptake of L-Td with different sizes was observed over time using a laser scanning confocal microscope (LSCM) equipped with a live cell chamber system. In addition, we conducted a pharmacokinetic study to examine the potential of L-Td as a carrier for in vivo tumor-targeted delivery of a low dose of doxorubicin (DOX). L-Td entered into the cells through endocytosis, and a specific DNA sequence of the L-Td ensures targeted entry into cancer cells. Compared with free DOX, DOX-loaded L-Td (DOX@L-Td) showed decreased clearance and increased initial concentration (C 0 ), half-life, and area under the curve (AUC), indicating that DOX@L-Td circulated in the blood stream for longer than free DOX. L-Td 17 , in particular, had beneficial effects owing to its ability to enhance tumor accumulation of DOX and reduce the cardiotoxicity caused by it through administration of a low dose of the drug., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In bacterial chemotaxis, the levels of phosphorylated CheY in association with FliM determine the sense of the flagella rotation, which in turn controls the bacterial swimming behavior. We report the 1.7Å resolution crystallographic structure of the Thermotoga maritima BeF(3)(-)-activated CheY in complex with the CheY-binding N-terminal region of FliM. Analysis of the structure in comparison to the previously reported Escherichia coli counterpart reveals that similar regions of H4-β5-H5 in CheY and the helix in FliM are used for the complex interfaces. Our structure also indicates that the correlated movement of Phe101 and Ser82 (F-S coupling) in T. maritima CheY upon phosphorylation and FliM binding, parallels that of Tyr106 and Thr87 (Y-T coupling) demonstrated in E. coli CheY. Furthermore, significant displacements of the β4-H4 loop in both CheYs impose a crucial role of this loop, which can be related to flagellar switch component binding or to propagating changes that is necessary during the CheY-mediated reversal of the motor., (Copyright © 2012 Elsevier B.V. All rights reserved.)