Research output: Contribution to journal › Article › peer-review
Structural basis for the recognition and processing of DNA containing bulky lesions by the mammalian nucleotide excision repair system. / Evdokimov, Alexey N.; Tsidulko, Alexandra Yu; Popov, Alexander V. et al.
In: DNA Repair, Vol. 61, 01.01.2018, p. 86-98.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Structural basis for the recognition and processing of DNA containing bulky lesions by the mammalian nucleotide excision repair system
AU - Evdokimov, Alexey N.
AU - Tsidulko, Alexandra Yu
AU - Popov, Alexander V.
AU - Vorobiev, Yury N.
AU - Lomzov, Alexander A.
AU - Koroleva, Lyudmila S.
AU - Silnikov, Vladimir N.
AU - Petruseva, Irina O.
AU - Lavrik, Olga I.
N1 - Copyright © 2017 Elsevier B.V. All rights reserved.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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.
AB - 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.
KW - DNA damage
KW - DNA repair
KW - Molecular dynamics
KW - Nucleotide excision repair
KW - Protein-DNA interaction
KW - MOLECULAR-MECHANISM
KW - COMPLEX
KW - EFFICIENCIES
KW - GROUP-C PROTEIN
KW - CROSS-LINKING
KW - ADDUCTS
KW - NUCLEIC-ACIDS
KW - DOUBLE-HELIX
KW - AMBER FORCE-FIELD
KW - DAMAGE RECOGNITION
KW - Temperature
KW - Cricetulus
KW - Humans
KW - Structure-Activity Relationship
KW - Nucleic Acid Conformation
KW - CHO Cells
KW - Nucleic Acid Denaturation
KW - Mammals/genetics
KW - DNA Replication
KW - DNA-Binding Proteins/chemistry
KW - Molecular Dynamics Simulation
KW - Animals
KW - DNA/chemistry
KW - DNA Repair
KW - DNA Damage
KW - Fluorescence Polarization
UR - http://www.scopus.com/inward/record.url?scp=85034946942&partnerID=8YFLogxK
U2 - 10.1016/j.dnarep.2017.10.010
DO - 10.1016/j.dnarep.2017.10.010
M3 - Article
C2 - 29103991
AN - SCOPUS:85034946942
VL - 61
SP - 86
EP - 98
JO - DNA Repair
JF - DNA Repair
SN - 1568-7864
ER -
ID: 8967736