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Molecular and Cellular Biology, October 2005, p. 8748-8754, Vol. 25, No. 19
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.19.8748-8754.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Human DNA Polymerase {iota} Promotes Replication through a Ring-Closed Minor-Groove Adduct That Adopts a syn Conformation in DNA

William T. Wolfle,1 Robert E. Johnson,1 Irina G. Minko,2 R. Stephen Lloyd,2 Satya Prakash,1 and Louise Prakash1*

Sealy Center for Molecular Science, University of Texas Medical Branch at Galveston, 6.104 Blocker Medical Research Building, 11th and Mechanic Streets, Galveston, Texas 77555-1061,1 Center for Research in Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, Oregon 972392

Received 16 June 2005/ Returned for modification 7 July 2005/ Accepted 11 July 2005

Acrolein, an {alpha},ß-unsaturated aldehyde, is generated in vivo as the end product of lipid peroxidation and from oxidation of polyamines. The reaction of acrolein with the N2 group of guanine in DNA leads to the formation of a cyclic adduct, {gamma}-hydroxy-1,N2-propano-2'-deoxyguanosine ({gamma}-HOPdG). Previously, we have shown that proficient replication through the {gamma}-HOPdG adduct can be mediated by the sequential action of human DNA polymerases (Pols) {iota} and {kappa}, in which Pol{iota} incorporates either pyrimidine opposite {gamma}-HOPdG, but Pol{kappa} extends only from the cytosine. Since {gamma}-HOPdG can adopt either a ring-closed cyclic form or a ring-opened form in DNA, to better understand the mechanisms that Pols {iota} and {kappa} employ to promote replication through this lesion, we have examined the ability of these polymerases to replicate through the structural analogs of {gamma}-HOPdG that are permanently either ring closed or ring opened. Our studies with these model adducts show that whereas the ring-opened form of {gamma}-HOPdG is not inhibitory to synthesis by human Pols {eta}, {iota}, or {kappa}, only Pol{iota} is able to incorporate nucleotides opposite the ring-closed form, which is known to adopt a syn conformation in DNA. From these studies, we infer that (i) Pols {eta}, {iota}, and {kappa} have the ability to proficiently replicate through minor-groove DNA lesions that do not perturb the Watson-Crick hydrogen bonding of the template base with the incoming nucleotide, and (ii) Pol{iota} can accommodate a minor-groove-adducted template purine which adopts a syn conformation in DNA and forms a Hoogsteen base pair with the incoming nucleotide.

* Corresponding author. Mailing address: Sealy Center for Molecular Science, University of Texas Medical Branch at Galveston, 6.104 Blocker Medical Research Building, 11th and Mechanic Streets, Galveston, TX 77555-1061. Phone: (409) 747-8601. Fax: (409) 747-8608. E-mail: l.prakash{at}utmb.edu.

Molecular and Cellular Biology, October 2005, p. 8748-8754, Vol. 25, No. 19
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.19.8748-8754.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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