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Processing of the abasic sites clustered with the benzo[a]pyrene adducts by the base excision repair enzymes. / Starostenko, Lidia V.; Rechkunova, Nadejda I.; Lebedeva, Natalia A. и др.
в: DNA Repair, Том 50, 01.02.2017, стр. 43-53.Результаты исследований: Научные публикации в периодических изданиях › статья › Рецензирование
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TY - JOUR
T1 - Processing of the abasic sites clustered with the benzo[a]pyrene adducts by the base excision repair enzymes
AU - Starostenko, Lidia V.
AU - Rechkunova, Nadejda I.
AU - Lebedeva, Natalia A.
AU - Lomzov, Alexander A.
AU - Koval, Vladimir V.
AU - Lavrik, Olga I.
N1 - Copyright © 2016 Elsevier B.V. All rights reserved.
PY - 2017/2/1
Y1 - 2017/2/1
N2 - The major enzyme in eukaryotic cells that catalyzes the cleavage of apurinic/apyrimidinic (AP or abasic) sites is AP endonuclease 1 (APE1) that cleaves the phosphodiester bond on the 5′-side of AP sites. We found that the efficiency of AP site cleavage by APE1 was affected by the benzo[a]pyrenyl-DNA adduct (BPDE-dG) in the opposite strand. AP sites directly opposite of the modified dG or shifted toward the 5′ direction were hydrolyzed by APE1 with an efficiency moderately lower than the AP site in the control DNA duplex, whereas AP sites shifted toward the 3′ direction were hydrolyzed significantly less efficiently. For all DNA structures except DNA with the AP site shifted by 3 nucleotides in the 3′ direction (AP+3-BP-DNA), hydrolysis was more efficient in the case of (+)-trans-BPDE-dG. Using molecular dynamic simulation, we have shown that in the complex of APE1 with the AP+3-BP-DNA, the BP residue is located within the DNA bend induced by APE1 and contacts the amino acids in the enzyme catalytic center and the catalytic metal ion. The geometry of the APE1 active site is perturbed more significantly by the trans-isomer of BPDE-dG that intercalates into the APE1-DNA complex near the cleaved phosphodiester bond. The ability of DNA polymerases β (Polβ), λ and ι to catalyze gap-filling synthesis in cooperation with APE1 was also analyzed. Polβ was shown to inhibit the 3′ → 5′ exonuclease activity of APE1 when both enzymes were added simultaneously and to insert the correct nucleotide into the gap arising after AP site hydrolysis. Therefore, further evidence for the functional cooperation of APE1 and Polβ in base excision repair was obtained.
AB - The major enzyme in eukaryotic cells that catalyzes the cleavage of apurinic/apyrimidinic (AP or abasic) sites is AP endonuclease 1 (APE1) that cleaves the phosphodiester bond on the 5′-side of AP sites. We found that the efficiency of AP site cleavage by APE1 was affected by the benzo[a]pyrenyl-DNA adduct (BPDE-dG) in the opposite strand. AP sites directly opposite of the modified dG or shifted toward the 5′ direction were hydrolyzed by APE1 with an efficiency moderately lower than the AP site in the control DNA duplex, whereas AP sites shifted toward the 3′ direction were hydrolyzed significantly less efficiently. For all DNA structures except DNA with the AP site shifted by 3 nucleotides in the 3′ direction (AP+3-BP-DNA), hydrolysis was more efficient in the case of (+)-trans-BPDE-dG. Using molecular dynamic simulation, we have shown that in the complex of APE1 with the AP+3-BP-DNA, the BP residue is located within the DNA bend induced by APE1 and contacts the amino acids in the enzyme catalytic center and the catalytic metal ion. The geometry of the APE1 active site is perturbed more significantly by the trans-isomer of BPDE-dG that intercalates into the APE1-DNA complex near the cleaved phosphodiester bond. The ability of DNA polymerases β (Polβ), λ and ι to catalyze gap-filling synthesis in cooperation with APE1 was also analyzed. Polβ was shown to inhibit the 3′ → 5′ exonuclease activity of APE1 when both enzymes were added simultaneously and to insert the correct nucleotide into the gap arising after AP site hydrolysis. Therefore, further evidence for the functional cooperation of APE1 and Polβ in base excision repair was obtained.
KW - Apurinic/apyrimidinic endonuclease 1
KW - Base excision repair
KW - Benzo[a]pyrene
KW - Clustered lesions
KW - DNA polymerases
KW - DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism
KW - Catalytic Domain
KW - DNA Polymerase beta/metabolism
KW - Humans
KW - 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide/metabolism
KW - Molecular Dynamics Simulation
KW - DNA Repair
KW - Protein Conformation
KW - DNA Damage
KW - Nucleic Acid Conformation
KW - DNA-Directed DNA Polymerase
KW - DNA Adducts/metabolism
KW - INCISION ACTIVITY
KW - EXONUCLEASE ACTIVITY
KW - HUMAN APURINIC ENDONUCLEASE
KW - CATALYTIC MECHANISM
KW - MOLECULAR-DYNAMICS SIMULATIONS
KW - HUMAN AP ENDONUCLEASE
KW - SOLUTION CONFORMATION
KW - LYASE ACTIVITY
KW - DNA-POLYMERASE-LAMBDA
KW - HUMAN APURINIC/APYRIMIDINIC ENDONUCLEASE
UR - http://www.scopus.com/inward/record.url?scp=85008331107&partnerID=8YFLogxK
U2 - 10.1016/j.dnarep.2016.12.007
DO - 10.1016/j.dnarep.2016.12.007
M3 - Article
C2 - 28065385
AN - SCOPUS:85008331107
VL - 50
SP - 43
EP - 53
JO - DNA Repair
JF - DNA Repair
SN - 1568-7864
ER -
ID: 8680637