PubMed · 11030316
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T Schettler, C Raffensperger, M McCally, P Orris, J Tickner. 2000-09-30. The DDT question.. https://doi.org/10.1016/s0140-6736(05)72883-x
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Unresolved DNA lesions trigger replication stress, forcing cancer cells to hijack DNA damage tolerance (DDT) networks, specifically translesion synthesis (TLS) and template switching, to sustain replication. While DDT prevents lethal fork collapse, error-prone TLS drives mutagenesis, tumor evolution, chemoresistance and radioresistance. Proliferating cell nuclear antigen post-translational modifications dynamically govern pathway selection. Cancer cells exploit this plasticity, creating actionable vulnerabilities such as postreplicative single-stranded DNA gaps. Emerging inhibitors targeting TLS polymerases, upstream regulators such as ubiquitin-specific peptidase 1 (USP1), and critical protein-protein interactions offer unprecedented opportunities for precision oncology. By integrating DDT inhibition with biomarkers such as homologous recombination deficiency and tumor mutational burden, we can drive synthetic lethality, sensitize tumors to genotoxic agents, suppress treatment-induced mutagenesis, and potentially enhance responses to immunotherapy.
Molecularly imprinting sol-gel materials for DDT using both a noncovalent and a covalent approach was examined. A nonpolar porous sol-gel network was created through the use of the bridged polysilsesquioxane, bis-(trimethoxysilylethyl)benzene (BTEB), as the principal sol-gel component. Noncovalent molecular imprinting was deemed unsuccessful, presumably because of the lack of strong intermolecular interactions that can be established between the DDT and the sol-gel precursor. A covalent imprinting strategy was employed by generating a sacrificial spacer through the reaction of two 3-isocyanatopropyltriethoxysilanes with one of two different template molecules: 4,4'-ethylenedianiline (EDA) or 4,4'-ethylidenebisphenol (EBP). After formation of the sol-gel, the bonds linking the spacer template to the matrix were cleaved in a manner that generated a pocket of the appropriate size bordered by amine groups that could aid in the binding of DDT through weak hydrogen bonding interactions. Experiments indicated that DDT could be bound selectively by such an approch. To generate a sensor, an environmentally sensitive fluorescent probe, 7-nitrobenz-2-oxa-1,3-diazole, (NBD) located adjacent to the DDT binding site was used to transduce the binding of analyte. EDA-imprinted sol-gels, deposited as films on glass microscope slides, were shown to quantitatively detect DDT in water to a limit-of-detection of 50 ppt with a response time of <60 s. Repeat measurements could be made with the same sensing films after rinsing with acetone between each measurement. The EDA sensing material was selective for DDT and other structurally similar molecules. However, the sensing film design was limited by the relatively minor changes in fluorescence intensity upon binding DDT. This situation may be remedied by an alternative methodology that can facilitate attachment of the NBD fluorophore in an optimal position proximal to the binding pocket.
There is a growing concern that environmental xenobiotics may be affecting human and wildlife health by disrupting normal endocrine function via interaction with steroid hormone receptors. Several of these persistent contaminants are chiral and may have enantiomer-specific biological properties. Previous experiments have demonstrated that (-)-o,p'-DDT enantiomer is a more active estrogen-mimic than the (+)-enantiomer in rats. However, these results have not been extrapolated to other biological systems. This study used a yeast-based assay to assess the enantiomer-specific transcriptional activity of DDT with the human estrogen receptor (hER). (+)-17beta-estradiol, racemic DDT and individual DDT enantiomers were added to yeast cultures and hER activity was measured by quantification of beta-galactosidase. The relative activity of o,p'-DDT was weak compared to estradiol. For o,p'-DDT, the (-)-enantiomer was the active estrogen mimic whereas the hER activity of (+)-o,p'-DDT was negligible. The presence of the (+)-enantiomer at relatively greater concentration decreased the transcriptional activity of (-)-o,p'-DDT. This data demonstrates the need to consider stereochemistry of environmental contaminants and their potential influence on biological responses.