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 -