Exploring damage recognition models in prokaryotic nucleotide excision repair with a benzo[a]pyrene-derived lesion in UvrB.
The UvrB protein is a central unit for damage recognition in the prokaryotic nucleotide excision repair system, which excises bulky DNA lesions. We have utilized molecular modeling and MD simulations based on crystal structures, mutagenesis, and fluorescence data, to model the 10R-(+)-cis-anti-B[a]P-N2-dG lesion, derived from the tumorigenic (+)-anti-B[a]PDE metabolite of benzo[a]pyrene, at different locations on the inner and outer strand in UvrB. Our results suggest that this lesion is accommodated on the inner strand where it might translocate through the tunnel created by the beta-hairpin and UvrB domain 1B and ultimately could be housed in the pocket behind the beta-hairpin prior to excision by UvrC. Lesions that vary in size and shape may be stopped at the gate to the tunnel, within the tunnel, or in the pocket when UvrC initiates excision. Common features of beta-hairpin intrusion between the two DNA strands and nucleotide flipping manifested in structures of prokaryotic and eukaryotic NER lesion recognition proteins are consistent with common recognition mechanisms, based on lesion-induced local thermodynamic distortion/destabilization and nucleotide flipping.
Jia
Lei
L
Department of Biology, New York University, 100 Washington Square East, Room 1009, New York, New York 10003, USA.
Kropachev
Konstantin
K
Ding
Shuang
S
Van Houten
Bennett
B
Geacintov
Nicholas E
NE
Broyde
Suse
S
D001564:Benzo(a)pyrene / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D002274:Carcinogens, Environmental / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D018736:DNA Adducts / Q000737:chemistry* / Q000378:metabolism*; D004249:DNA Damage; D004265:DNA Helicases / Q000737:chemistry* / Q000378:metabolism*; D004260:DNA Repair / Q000502:physiology*; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000378:metabolism*; D046911:Macromolecular Substances; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
D002274:Carcinogens, Environmental; D018736:DNA Adducts; D029968:Escherichia coli Proteins; D046911:Macromolecular Substances; C058093:UvrB protein, E coli; C056612:benzo(a)pyrene-DNA adduct; D001564:Benzo(a)pyrene; D004265:DNA Helicases
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