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Structural Insights into the Recognition of N 2 ‐Aryl‐ and C8‐Aryl DNA Lesions by the Repair Protein XPA/Rad14
Author(s) -
Ebert Charlotte,
Simon Nina,
Schneider Sabine,
Carell Thomas
Publication year - 2017
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201700169
Subject(s) - duplex (building) , nucleobase , chemistry , aryl , dna , adduct , dna repair , stereochemistry , base pair , dna damage , stacking , electrophile , biochemistry , alkyl , organic chemistry , catalysis
Aromatic amines are strongly carcinogenic. They are activated in the liver to give reactive nitrenium ions that react with nucleobases within the DNA duplex. The reaction occurs predominantly at the C8 position of the dG base, thereby giving C8‐acetyl‐aryl‐ or C8‐aryl‐dG adducts in an electrophilic aromatic substitution reaction. Alternatively, reaction with the exocyclic 2‐NH 2 group is observed. Although the C8 adducts retain base‐pairing properties, base pairing is strongly compromised in the case of the N 2 adducts. Here we show crystal structures of two DNA lesions, N 2 ‐acetylnaphthyl‐dG and C8‐fluorenyl‐dG, within a DNA duplex recognized by the repair protein Rad14. The structures confirm that two molecules of the repair protein recognize the lesion and induce a 72 or 78° kink at the site of the damage. Importantly, the same overall kinked structure is induced by binding of the repair proteins, although the structurally different lesions result in distinct stacking interactions of the lesions within the duplex. The results suggest that the repair protein XPA/Rad14 is a sensor that recognizes flexibility. The protein converts the information that structurally different lesions are present in the duplex into a unifying sharply kinked recognition motif.