Gene/Protein Disease Symptom Drug Enzyme Compound
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Human exposure to arsenic in drinking water is known to be associated with the development of bladder, lung, kidney, and skin cancers. The molecular mechanisms underlying the carcinogenic effects of arsenic species remain incompletely understood. DNA interstrand cross-links (ICLs) are among the most cytotoxic type of DNA lesions that block DNA replication and transcription, and these lesions can be induced by endogenous metabolism and by exposure to exogenous agents. Fanconi anemia (FA) is a congenital disorder manifested with elevated sensitivity toward DNA interstrand cross-linking agents, and monoubiquitination of FANCD2 by FANCL is a crucial step in FA-mediated DNA repair. Here, we demonstrated that As3+ could bind to the PHD/RING finger domain of FANCL in vitro and in cells. This binding led to compromised ubiquitination of FANCD2 in cells and diminished recruitment of FANCD2 to chromatin and DNA damage sites induced by 4,5',8-trimethylpsoralen plus UVA irradiation. Furthermore, clonogenic survival assay results showed that arsenite coexposure rendered cells more sensitive toward DNA interstrand cross-linking agents. Together, our study suggested that arsenite may compromise genomic stability via perturbation of the Fanconi anemia pathway, thereby conferring its carcinogenic effect.
ACS Chem Biol 2017 07 21
PMID:Arsenite Binds to the RING Finger Domain of FANCL E3 Ubiquitin Ligase and Inhibits DNA Interstrand Crosslink Repair. 2853 27

Phenylketonuria (PKU) is a common disease in congenital disorder of amino acid metabolism, which can lead to intellectual disability, seizures, behavioral problems, and mental disorders. We report herein a facile method to screen for PKU by the measurements of its metabolites (markers). In this work, a disposable electrochemical microsensor modified with a ZIF (zeolitic imidazolate framework)-based nanocomposite is constructed, in which ZIF-67 crystals are encapsulated with PtPd alloy nanoparticles (NPs) forming the nanocomposite (PtPd@ZIF-67). According to electrochemical measurements, the PtPd@ZIF-67-modified microsensor shows good responses and selectivity to phenylpyruvic acid and phenylacetic acid, while almost no response toward other amino acid analogues is observed. Here, a new sensing mechanism based on the acylation reaction between the imidazole linker in ZIF-67 and carboxyl in PKU markers has been proposed and verified through the Fourier-transform infrared spectroscopy study. Moreover, the encapsulated PtPd NPs elevate the electron transfer capability of the PtPd@ZIF-67-modified microsensor and further improve the electrochemical sensing performance. Finally, we demonstrate that the developed PtPd@ZIF-67-modified microsensor has the possibility to sensing of PKU markers with high response and good specificity and may be extended to exploit the point-of-care rapid PKU screening.
ACS Appl Mater Interfaces 2019 Jun 12
PMID:Detection of Phenylketonuria Markers Using a ZIF-67 Encapsulated PtPd Alloy Nanoparticle (PtPd@ZIF-67)-Based Disposable Electrochemical Microsensor. 3109 5