Structural basis for the recognition and processing of DNA containing bulky lesions by the mammalian nucleotide excision repair system
| Autor: | I. O. Petruseva, Olga I. Lavrik, Vladimir N. Silnikov, Lyudmila S. Koroleva, A. N. Evdokimov, Alexandra Y. Tsidulko, Alexander V. Popov, Yury N. Vorobiev, Alexander A. Lomzov |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
DNA Replication
0301 basic medicine DNA Repair DNA repair DNA damage Stereochemistry Stacking Fluorescence Polarization CHO Cells Molecular Dynamics Simulation Biology Nucleic Acid Denaturation Biochemistry Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Cricetulus Animals Humans Protein–DNA interaction Molecular Biology Mammals Temperature DNA replication Substrate (chemistry) DNA Cell Biology DNA-Binding Proteins 030104 developmental biology chemistry Nucleic Acid Conformation DNA Damage Nucleotide excision repair |
| Zdroj: | DNA Repair. 61:86-98 |
| ISSN: | 1568-7864 |
| Popis: | Mammalian nucleotide excision repair (NER) eliminates the broadest diversity of bulky lesions from DNA with wide specificity. However, the double incision efficiency for structurally different adducts can vary over several orders of magnitude. Therefore, great attention is drawn to the question of the relationship among structural properties of bulky DNA lesions and the rate of damage elimination. This paper studies the properties of several structurally diverse synthetic (model) DNAs containing bulky modifications. Model DNAs have been designed using modified nucleosides (exo-N-{2-N-[N-(4-azido-2,5-difluoro-3-chloropyridin-6-yl)-3-aminopropionyl]aminoethyl}-2'-deoxycytidine (Fap-dC) and 5-{1-[6-(5[6]-fluoresceinylcarbomoyl)hexanoyl]-3-aminoallyl}-2'-deoxyuridine (Flu-dU)) and the nonnucleosidic reagent N-[6-(9-antracenylcarbomoyl)hexanoyl]-3-amino-1,2-propandiol (nAnt). The impact of these lesions on spatial organization and stability of the model DNA was evaluated. Their affinity for the damage sensor XPC was also studied. It was expected, that the values of melting temperature decrease, bending angles and KD values clearly define the row of model DNA substrate properties such as Flu-dU-DNA>>nAnt≈Fap-dC-DNA. Unexpectedly the experimentally estimated levels of the substrate properties were actually in the row: nAnt-DNA>>Flu-dU-DNA>>Fap-dC-DNA. Molecular dynamics simulations have revealed structural and energetic bases for the discrepancies observed. DNA destabilization patterns plotted explain these results on a structural basis in terms of differences in dynamic perturbations of stacking interactions. |
| Databáze: | OpenAIRE |
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