A coordinated and faithful DNA damage response is of central importance for maintaining genomic integrity and survival. Here, we show that exposure of human cells to benzo(a)pyrene 9,10-diol-7,8-epoxide (BPDE), the active metabolite of benzo(a)pyrene (B(a)P), which represents a most important carcinogen formed during food preparation at high temperature, smoking and by incomplete combustion processes, causes a prompt and sustained upregulation of the DNA repair genes DDB2, XPC, XPF, XPG and POLH. Induction of these repair factors on RNA and protein level enhanced the removal of BPDE adducts from DNA and protected cells against subsequent BPDE exposure. However, through the induction of POLH the mutation frequency in the surviving cells was enhanced. Activation of these adaptive DNA repair genes was also observed upon B(a)P treatment of MCF7 cells and in buccal cells of human volunteers after cigarette smoking. Our data provide a rational basis for an adaptive response to polycyclic aromatic hydrocarbons, which occurs however at the expense of mutations that may drive cancer formation.
In a three-dimensional (3D) representation, each protein
molecule
displays a specific pattern of chemical and topological features,
which are altered during its misfolding and aggregation pathway. Generating
a recognizable fingerprint from such features could provide an enticing
approach not only to identify these biomolecules but also to gain
clues regarding their folding state and the occurrence of pathologically
lethal misfolded aggregates. We report here a universal strategy to
generate a fluorescent fingerprint from biomolecules by employing
the pan-selective molecular recognition feature of a cucurbit[7]uril
(CB[7]) macrocyclic receptor. We implemented a direct sensing strategy
by covalently tethering CB[7] with a library of fluorescent reporters.
When CB[7] recognizes the chemical and geometrical features of a biomolecule,
it brings the tethered fluorophore into the vicinity, concomitantly
reporting the nature of its binding microenvironment through a change
in their optical signature. The photophysical properties of the fluorophores
allow a multitude of probing modes, while their structural features
provide additional binding diversity, generating a distinct fluorescence
fingerprint from the biomolecule. We first used this strategy to rapidly
discriminate a diverse range of protein analytes. The macrocyclic
sensor was then applied to probe conformational changes in the protein
structure and identify the formation of oligomeric and fibrillar species
from misfolded proteins. Notably, the sensor system allowed us to
differentiate between different self-assembled forms of the disease-specific
amyloid-β (Aβ) aggregates and segregated them from other
generic amyloid structures with a 100% identification accuracy. Ultimately,
this sensor system predicted clinically relevant changes by fingerprinting
serum samples from a cohort of pregnant women.
The pH‐responsive nature of two self‐assembled NDI‐peptide amphiphile conjugates is reported. The diethoxy substituted NDI showed a pH‐dependent assembly behaviour, as expected. In contrast, the isopropylamino‐ and ethoxy‐substituted NDI based supramolecular polymer was stable at acidic and basic aqueous conditions. This finding highlights how subtle changes in the molecular design of π‐stacked chromophore‐peptide conjugates have a drastic impact on their equilibrium structure and ultimately functional properties.
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