Repair of hydantoin lesions and their amine adducts in DNA by base and nucleotide excision repair.
An important feature of the common DNA oxidation product 8-oxo-7,8-dihydroguanine (OG) is its susceptibility to further oxidation that produces guanidinohydantoin (Gh) and spiroiminodihydantoin (Sp) lesions. In the presence of amines, G or OG oxidation produces hydantoin amine adducts. Such adducts may form in cells via interception of oxidized intermediates by protein-derived nucleophiles or naturally occurring amines that are tightly associated with DNA. Gh and Sp are known to be substrates for base excision repair (BER) glycosylases; however, large Sp-amine adducts would be expected to be more readily repaired by nucleotide excision repair (NER). A series of Sp adducts differing in the size of the attached amine were synthesized to evaluate the relative processing by NER and BER. The UvrABC complex excised Gh, Sp, and the Sp-amine adducts from duplex DNA, with the greatest efficiency for the largest Sp-amine adducts. The affinity of UvrA for all of the lesion duplexes was found to be similar, whereas the efficiency of UvrB loading tracked with the efficiency of UvrABC excision. In contrast, the human BER glycosylase NEIL1 exhibited robust activity for all Sp-amine adducts irrespective of size. These studies suggest that both NER and BER pathways mediate repair of a diverse set of hydantoin lesions in cells.
Department of Chemistry, University of California, Davis , One Shields Avenue, Davis, California 95616, United States.
Paige L
PL
McKibbin
Aaron M
AM
Fleming
Mohammad Atif
MA
Towheed
Bennett
B
Van Houten
Cynthia J
CJ
Burrows
Sheila S
SS
David
D000588:Amines / Q000737:chemistry*; D001483:Base Sequence; D004247:DNA / Q000737:chemistry* / Q000235:genetics; D004260:DNA Repair; D006801:Humans; D006827:Hydantoins / Q000737:chemistry*; D008969:Molecular Sequence Data; D015394:Molecular Structure
D000588:Amines; D006827:Hydantoins; D004247:DNA