title: Binding of the human nucleotide excision repair proteins XPA and XPC/HR23B to the 5R-thymine glycol lesion and structure of the cis-(5R,6S) thymine glycol epimer in the 5'-GTgG-3' sequence: destabilization of two base pairs at the lesion site.
abstract: The 5R thymine glycol (5R-Tg) DNA lesion exists as a mixture of cis-(5R,6S) and trans-(5R,6R) epimers; these modulate base excision repair. We examine the 7:3 cis-(5R,6S):trans-(5R,6R) mixture of epimers paired opposite adenine in the 5'-GTgG-3' sequence with regard to nucleotide excision repair. Human XPA recognizes the lesion comparably to the C8-dG acetylaminoflourene (AAF) adduct, whereas XPC/HR23B recognition of Tg is superior. 5R-Tg is processed by the Escherichia coli UvrA and UvrABC proteins less efficiently than the C8-dG AAF adduct. For the cis-(5R, 6S) epimer Tg and A are inserted into the helix, remaining in the Watson-Crick alignment. The Tg N3H imine and A N(6) amine protons undergo increased solvent exchange. Stacking between Tg and the 3'-neighbor G*C base pair is disrupted. The solvent accessible surface and T(2) relaxation of Tg increases. Molecular dynamics calculations predict that the axial conformation of the Tg CH(3) group is favored; propeller twisting of the Tg*A pair and hydrogen bonding between Tg OH6 and the N7 atom of the 3'-neighbor guanine alleviate steric clash with the 5'-neighbor base pair. Tg also destabilizes the 5'-neighbor G*C base pair. This may facilitate flipping both base pairs from the helix, enabling XPC/HR23B recognition prior to recruitment of XPA.
authors.affiliation: Department of Chemistry and Center in Molecular Toxicology, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Brown
authors.forename: Marina
authors.initials: M
authors.lastname: Roginskaya
authors.forename: Yue
authors.initials: Y
authors.lastname: Zou
authors.forename: Alvin
authors.initials: A
authors.lastname: Altamirano
authors.forename: Ashis K
authors.initials: AK
authors.lastname: Basu
authors.forename: Michael P
authors.initials: MP
authors.lastname: Stone
mesh_terms: D020029:Base Pairing; D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D045643:DNA Repair Enzymes / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004706:Endodeoxyribonucleases / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011522:Protons; D013237:Stereoisomerism; D013941:Thymine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D051760:Xeroderma Pigmentosum Group A Protein / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D011522:Protons; C513287:RAD23B protein, human; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; C029389:thymine glycol; D004247:DNA; D004706:Endodeoxyribonucleases; C036385:endodeoxyribonuclease uvrABC; D045643:DNA Repair Enzymes; D013941:Thymine