title: Destabilization of DNA duplexes by oxidative damage at guanine: implications for lesion recognition and repair.
abstract: We have used molecular dynamics simulations to study the structure and dynamics of a range of DNA duplexes containing the 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapydG) lesion that can result from oxidative damage at guanine. Compared to the corresponding undamaged DNA duplexes, FapydG-containing duplexes show little gross structural changes-the damaged base remains stacked in to the DNA double helix and retains hydrogen bonds to its cytosine partner. However, the experimentally observed reduction in DNA stability that accompanies lesion formation can be explained by a careful energetic analysis of the simulation data. Irrespective of the nature of the base pairs on either side of the lesion site, conversion of a guanine to a FapydG base results in increased dynamical flexibility in the base (but not in the DNA as a whole) that significantly weakens its hydrogen-bonding interactions. Surprisingly, the stacking interactions with its neighbours are not greatly altered. The formamido group adopts a non-planar conformation that can interact significantly and in a sequence-dependent manner with its 3'-neighbour. We conclude that the recognition of FapydG lesions by the repair protein formamidopyrimidine-DNA glycosylase probably does not involve the protein capturing an already-extrahelical FapydG base, but rather it relies on detecting alterations to the DNA structure and flexibility created by the lesion site.
authors.affiliation: School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham, Nottingham, UK.
authors.forename: Supat
authors.initials: S
authors.lastname: Jiranusornkul
authors.forename: Charles A
authors.initials: CA
authors.lastname: Laughton
mesh_terms: D003198:Computer Simulation; D004247:DNA / Q000737:chemistry*; D004249:DNA Damage; D004260:DNA Repair; D005559:Formamides / Q000737:chemistry*; D005663:Furans / Q000737:chemistry*; D006147:Guanine / Q000737:chemistry*; D046911:Macromolecular Substances / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000737:chemistry*
chemical_list: D005559:Formamides; D005663:Furans; D046911:Macromolecular Substances; C435881:N6-(2-deoxy-erythro-pentofuranosyl)-2,6-diamino-4-hydroxy-5-formamidopyrimidine; D011743:Pyrimidines; D006147:Guanine; D004247:DNA
references.citation: Carcinogenesis. 1997 Feb;18(2):271-7
references.pmid: 9054618
references.citation: J Photochem Photobiol B. 2004 Feb 20;73(3):167-75
references.pmid: 14975405
references.citation: DNA Repair (Amst). 2007 Apr 1;6(4):544-59
references.pmid: 17112792
references.citation: Chem Res Toxicol. 2002 Nov;15(11):1460-5
references.pmid: 12437337
references.citation: Biochemistry. 2006 Sep 12;45(36):10886-94
references.pmid: 16953574
references.citation: J Biochem Mol Biol. 2003 Jan 31;36(1):12-9
references.pmid: 12542970
references.citation: J Am Chem Soc. 2002 Jun 26;124(25):7272-3
references.pmid: 12071727
references.citation: Biochemistry. 2004 Oct 26;43(42):13397-403
references.pmid: 15491146
references.citation: Acc Chem Res. 2000 Dec;33(12):889-97
references.pmid: 11123888
references.citation: Int J Radiat Biol. 1993 Dec;64(6):645-50
references.pmid: 7903331
references.citation: Methods. 2007 Jun;42(2):196-203
references.pmid: 17472901
references.citation: J Biol Chem. 2005 Dec 9;280(49):40544-51
references.pmid: 16221681
references.citation: J Comput Chem. 2004 Jan 30;25(2):238-50
references.pmid: 14648622
references.citation: Chem Rev. 1998 May 7;98(3):1109-1152
references.pmid: 11848927
references.citation: Angew Chem Int Ed Engl. 2003 Oct 20;42(40):4947-51
references.pmid: 14579447
references.citation: Annu Rev Phys Chem. 2000;51:435-71
references.pmid: 11031289
references.citation: Chem Res Toxicol. 2000 Jul;13(7):541-9
references.pmid: 10898585
references.citation: Biochemistry. 1998 Mar 31;37(13):4374-87
references.pmid: 9521757
references.citation: Cancer Res. 1993 Mar 15;53(6):1269-72
references.pmid: 8383005
references.citation: J Am Chem Soc. 2001 Dec 19;123(50):12658-63
references.pmid: 11741431
references.citation: J Am Chem Soc. 2005 Dec 28;127(51):18143-9
references.pmid: 16366567
references.citation: Biochemistry. 2003 Aug 19;42(32):9755-60
references.pmid: 12911318
references.citation: Carcinogenesis. 1997 Dec;18(12):2385-91
references.pmid: 9450486
references.citation: J Biol Chem. 2004 Oct 15;279(42):44074-83
references.pmid: 15249553
references.citation: Carcinogenesis. 2000 Mar;21(3):361-70
references.pmid: 10688856
references.citation: Mutat Res. 2004 Sep;567(1):1-61
references.pmid: 15341901
references.citation: Nucleic Acids Res. 2004 Aug 10;32(14):4269-80
references.pmid: 15304564
references.citation: J Am Chem Soc. 2002 Jun 26;124(25):7278-9
references.pmid: 12071730
references.citation: J Am Chem Soc. 2001 Sep 5;123(35):8636-7
references.pmid: 11525688