The N-(2-deoxy-d-erythro-pentofuranosyl)-urea DNA lesion forms following hydrolytic fragmentation of cis-5R,6S- and trans-5R,6R-dihydroxy-5,6-dihydrothymidine (thymine glycol, Tg) or from oxidation of 7,8-dihydro-8-oxo-deoxyguanosine (8-oxodG) and subsequent hydrolysis. It interconverts between α and β deoxyribose anomers. Synthetic oligodeoxynucleotides containing this adduct are efficiently incised by unedited (K242) and edited (R242) forms of the hNEIL1 glycosylase. The structure of a complex between the active site unedited mutant CΔ100 P2G hNEIL1 (K242) glycosylase and double-stranded (ds) DNA containing a urea lesion reveals a pre-cleavage intermediate, in which the Gly2 N-terminal amine forms a conjugate with the deoxyribose C1′ of the lesion, with the urea moiety remaining intact. This structure supports a proposed catalytic mechanism in which Glu3-mediated protonation of O4′ facilitates attack at deoxyribose C1′. The deoxyribose is in the ring-opened configuration with the O4′ oxygen protonated. The electron density of Lys242 suggests the ‘residue 242-in conformation’ associated with catalysis. This complex likely arises because the proton transfer steps involving Glu6 and Lys242 are hindered due to Glu6-mediated H-bonding with the Gly2 and the urea lesion. Consistent with crystallographic data, biochemical analyses show that the CΔ100 P2G hNEIL1 (K242) glycosylase exhibits a residual activity against urea-containing dsDNA.
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Stavros, Kallie M. ; Hawkins, Edward K. ; Rizzo, Carmelo J. ; Stone, Michael P. ( , Chemical Research in Toxicology)
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Kowal, Ewa A. ; Wickramaratne, Susith ; Kotapati, Srikanth ; Turo, Michael ; Tretyakova, Natalia ; Stone, Michael P. ( , Chemical Research in Toxicology)
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Szulik, Marta W. ; Pallan, Pradeep S. ; Nocek, Boguslaw ; Voehler, Markus ; Banerjee, Surajit ; Brooks, Sonja ; Joachimiak, Andrzej ; Egli, Martin ; Eichman, Brandt F. ; Stone, Michael P. ( , Biochemistry)