Influence of C-5 substituted cytosine and related nucleoside analogs on the formation of benzo[a]pyrene diol epoxide-dG adducts at CG base pairs of DNA.
Endogenous 5-methylcytosine ((Me)C) residues are found at all CG dinucleotides of the p53 tumor suppressor gene, including the mutational 'hotspots' for smoking induced lung cancer. (Me)C enhances the reactivity of its base paired guanine towards carcinogenic diolepoxide metabolites of polycyclic aromatic hydrocarbons (PAH) present in cigarette smoke. In the present study, the structural basis for these effects was investigated using a series of unnatural nucleoside analogs and a representative PAH diolepoxide, benzo[a]pyrene diolepoxide (BPDE). Synthetic DNA duplexes derived from a frequently mutated region of the p53 gene (5'-CCCGGCACCC GC[(15)N(3),(13)C(1)-G]TCCGCG-3', + strand) were prepared containing [(15)N(3), (13)C(1)]-guanine opposite unsubstituted cytosine, (Me)C, abasic site, or unnatural nucleobase analogs. Following BPDE treatment and hydrolysis of the modified DNA to 2'-deoxynucleosides, N(2)-BPDE-dG adducts formed at the [(15)N(3), (13)C(1)]-labeled guanine and elsewhere in the sequence were quantified by mass spectrometry. We found that C-5 alkylcytosines and related structural analogs specifically enhance the reactivity of the base paired guanine towards BPDE and modify the diastereomeric composition of N(2)-BPDE-dG adducts. Fluorescence and molecular docking studies revealed that 5-alkylcytosines and unnatural nucleobase analogs with extended aromatic systems facilitate the formation of intercalative BPDE-DNA complexes, placing BPDE in a favorable orientation for nucleophilic attack by the N(2) position of guanine.
Department of Medicinal Chemistry and the Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Rebecca
R
Guza
Delshanee
D
Kotandeniya
Kristopher
K
Murphy
Thakshila
T
Dissanayake
Chen
C
Lin
George Madalin
GM
Giambasu
Rahul R
RR
Lad
Filip
F
Wojciechowski
Shantu
S
Amin
Shana J
SJ
Sturla
Robert H E
RH
Hudson
Darrin M
DM
York
Ryszard
R
Jankowiak
Roger
R
Jones
Natalia Y
NY
Tretyakova
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000031:analogs & derivatives* / Q000737:chemistry; D020029:Base Pairing; D002851:Chromatography, High Pressure Liquid; D003596:Cytosine / Q000031:analogs & derivatives*; D018736:DNA Adducts / Q000737:chemistry*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000737:chemistry; D016158:Genes, p53; D006147:Guanine / Q000737:chemistry; D007553:Isotope Labeling; D008958:Models, Molecular; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis / Q000737:chemistry; D013050:Spectrometry, Fluorescence; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry
D018736:DNA Adducts; D009838:Oligodeoxyribonucleotides; C418058:benzo(a)pyrene 7,8-diol-9,10-epoxide-N2-deoxyguanosine; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D006147:Guanine; D003596:Cytosine; D003849:Deoxyguanosine
Science. 1996 Oct 18;274(5286):430-2
8832894
Chem Res Toxicol. 2004 Sep;17(9):1236-44
15377157
Carcinogenesis. 1989 Jun;10(6):1131-7
2720906
Curr Top Microbiol Immunol. 2000;249:1-19
10802935
Chem Res Toxicol. 2001 Aug;14(8):1058-70
11511180
Trends Endocrinol Metab. 2000 May-Jun;11(4):142-8
10754536
Mol Cell Biol. 1997 Dec;17(12):7069-76
9372938
Biophys Chem. 1995 Nov;56(3):281-96
7578905
Biochemistry. 2001 Apr 3;40(13):3859-68
11300765
Chem Biol. 1999 Jul;6(7):461-71
10381403
Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1371-5
8108418
J Am Chem Soc. 2003 Dec 10;125(49):14990-1
14653725
Chem Res Toxicol. 2007 Oct;20(10):1379-87
17867647
Nucleic Acids Res. 2005 May 25;33(9):3057-64
15917437
Biochemistry. 2005 Feb 15;44(6):2197-207
15697245
Chem Res Toxicol. 2007 Aug;20(8):1192-9
17630708
Biochem Biophys Res Commun. 1987 Oct 29;148(2):790-4
3689373
Biochemistry. 1996 Jul 30;35(30):9850-63
8703959
Nucleic Acids Res. 2000 Dec 1;28(23):4717-24
11095682
Nucleic Acids Res. 2006 Jan 13;34(2):417-25
16415180
Biochem Biophys Res Commun. 1984 Jul 18;122(1):33-9
6430294
Biopolymers. 1993 Nov;33(11):1659-75
8241426
J Org Chem. 2003 Oct 31;68(22):8657-61
14575499
J Am Chem Soc. 2007 Dec 12;129(49):15218-32
17999503
Nature. 1977 Sep 22;269(5626):348-50
904688
Biochemistry. 2004 Jan 20;43(2):540-9
14717610
Nucleic Acids Res. 1982 Apr 24;10(8):2709-21
7079182
Nature. 1986 May 15-21;321(6067):209-13
2423876
J Am Chem Soc. 2007 Apr 25;129(16):4882-3
17402738
Biophys J. 2007 Jun 1;92(11):3817-29
17351000
Oncogene. 2002 Oct 21;21(48):7435-51
12379884
Chem Res Toxicol. 2002 Mar;15(3):438-44
11896693
Biochemistry. 1977 Aug 9;16(16):3680-7
889815
Chem Res Toxicol. 2004 Mar;17(3):330-9
15025503
IARC Monogr Eval Carcinog Risk Chem Hum. 1983 Dec;32:1-453
6586639
Carcinogenesis. 2001 Mar;22(3):367-74
11238174
Carcinogenesis. 1989 Jul;10(7):1333-5
2500269
Biochemistry. 1997 Oct 28;36(43):13263-9
9341216
Biochemistry. 1992 Aug 25;31(33):7595-9
1510946
Mutat Res. 2000 May 30;450(1-2):155-66
10838140
J Biol Chem. 1982 Sep 10;257(17):10479-85
6286655
Chem Res Toxicol. 2004 Jun;17(6):731-41
15206894
Biochemistry. 1982 Apr 13;21(8):1864-9
6805508
Dis Markers. 2007;23(1-2):1-3
17325422
J Mol Graph Model. 2006 Dec;25(4):423-33
16580853
Chem Res Toxicol. 1994 Jan-Feb;7(1):98-109
8155833
Biochem Biophys Res Commun. 1999 Jan 8;254(1):114-9
9920742
Nucleic Acids Res. 2004 Aug 09;32(14):4100-8
15302911
Biochemistry. 2000 Aug 29;39(34):10431-8
10956033
Biochemistry. 2005 Jan 25;44(3):1054-66
15654762
J Am Chem Soc. 2008 Sep 24;130(38):12574-5
18761442
Chem Commun (Camb). 2006 Sep 21;(35):3665-75
17047807
Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3893-8
9108075
Adv Cancer Res. 1983;40:1-30
6197868
Chem Res Toxicol. 1997 Feb;10(2):111-46
9049424
Cancer Biochem Biophys. 1986 Dec;9(1):67-73
3815321
J Org Chem. 2004 May 28;69(11):3979-82
15153038
Biochemistry. 2002 Jul 30;41(30):9535-44
12135376
J Mol Biol. 2005 Mar 4;346(4):951-65
15701509
J Chem Theory Comput. 2007 Jul;3(4):1464-75
26633217
Biochemistry. 2003 Mar 4;42(8):2456-66
12600213
Biochemistry. 1992 Jun 16;31(23):5245-52
1606148
Biopolymers. 1987;26 Suppl:S145-60
3580495
Chem Res Toxicol. 1990 Jan-Feb;3(1):39-46
2131823
Oncogene. 1995 Apr 20;10(8):1493-9
7731703
Biochemistry. 1994 Mar 29;33(12):3649-59
8142363
Nucleic Acids Res. 2007;35(5):1555-68
17287290
Chem Res Toxicol. 1994 Mar-Apr;7(2):125-9
8199298
Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1749-54
9050850
Biochemistry. 1988 Nov 1;27(22):8380-7
3149504
Theor Chem Acc. 2009 Mar 1;122(3):179-188
19890472
Biochim Biophys Acta. 1990 May 24;1049(1):1-8
1694091
Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1914-8
1311854
Cancer Sci. 2004 Jan;95(1):1-6
14720319
J Phys Chem B. 2007 Feb 22;111(7):1846-57
17256983
Biochemistry. 1997 Dec 2;36(48):14868-73
9398209