Catalogo Articoli (Spogli Riviste)

OPAC HELP

Titolo:
Molecular topology of polycyclic aromatic carcinogens determines DNA adduct conformation: A link to tumorigenic activity
Autore:
Lin, CH; Huang, XW; Kolbanovskii, A; Hingerty, BE; Amin, S; Broyde, S; Geacintov, NE; Patel, DJ;
Indirizzi:
Mem Sloan Kettering Canc Ctr, Cellular Biochem & Biophys Program, New York, NY 10021 USA Mem Sloan Kettering Canc Ctr New York NY USA 10021 New York, NY 10021 USA NYU, Dept Biol, New York, NY 10003 USA NYU New York NY USA 10003NYU, Dept Biol, New York, NY 10003 USA Oak Ridge Natl Lab, Div Life Sci, Oak Ridge, TN 37831 USA Oak Ridge Natl Lab Oak Ridge TN USA 37831 fe Sci, Oak Ridge, TN 37831 USA Amer Hlth Fdn, Valhalla, NY 10595 USA Amer Hlth Fdn Valhalla NY USA 10595Amer Hlth Fdn, Valhalla, NY 10595 USA NYU, Dept Chem, New York, NY 10003 USA NYU New York NY USA 10003NYU, Dept Chem, New York, NY 10003 USA
Titolo Testata:
JOURNAL OF MOLECULAR BIOLOGY
fascicolo: 5, volume: 306, anno: 2001,
pagine: 1059 - 1080
SICI:
0022-2836(20010309)306:5<1059:MTOPAC>2.0.ZU;2-U
Fonte:
ISI
Lingua:
ENG
Soggetto:
EPOXIDE-DEOXYADENOSINE ADDUCTS; BENZOPYRENE DIOL EPOXIDES; CANCER MUTATIONAL HOTSPOTS; RAS CODON-61 SEQUENCE; FEMALE CD RATS; FJORD REGION; EXCISION-REPAIR; MAMMARY CARCINOGENICITY; MODIFIED DEOXYGUANOSINE; DIHYDRODIOL EPOXIDES;
Keywords:
BPh-N-2-G adducts intercalate without base-pair disruption; "fjord" BPh-N-2-G versus "bay" BP-N-2-G adducts; "fjord" BPh-N-2-G versus "fjord" BPh-N-6-A adducts; stereoisomer-related adduct directionality;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
47
Recensione:
Indirizzi per estratti:
Indirizzo: Patel, DJ Mem Sloan Kettering Canc Ctr, Cellular Biochem & Biophys Program, 1275 York Ave, New York, NY 10021 USA Mem Sloan Kettering Canc Ctr 1275 York Ave New York NY USA 10021
Citazione:
C.H. Lin et al., "Molecular topology of polycyclic aromatic carcinogens determines DNA adduct conformation: A link to tumorigenic activity", J MOL BIOL, 306(5), 2001, pp. 1059-1080

Abstract

We report below on the solution structures of stereoisomeric "fjord" region trans-anti-benzo[c]phenanthrene-N-2-guanine (designated (BPh)G) adducts positioned opposite cytosine within the (C-(BPh)G-C) (G-C-G) sequence context. We observe intercalation of the phenanthrenyl ring with stereoisomer-dependent directionality, without disruption of the modified (BPh)G.C base-pair. Intercalation occurs to the 5' side of the modified strand for the 1S stereoisomeric adduct and to the 3' side for the 1R stereoisomeric adduct, with the S and R-trans-isomers related to one another by inversion in a mirror plane at all four chiral carbon atoms on the benzylic ring. Intercalationof the fjord region BPh ring into the helix without disruption of the modified base-pair is achieved through buckling of the (BPh)GC base-pair, displacement of the linkage bond from the plane of the (BPh)G base, adaptation of a chair pucker by the BPh benzylic ring and the propeller-like deviation from planarity of the BPh phenanthrenyl ring. It is noteworthy that intercalation without basepair disruption occurs from the minor groove side for S and R-trans-anti BPh-N-2-guanine adducts opposite C, in contrast to our previous demonstration of intercalation without modified base-pair disruption from the major groove side for S and R-trans-anti BPh-N-6-adenine adducts opposite T. Further, these results on fjord region 1S and 1R-trans-anti (BPh)G adducts positioned opposite C are in striking contrast to earlier research with "bay" region benzo[a]pyrene-N-2-guanine (designated (BP)G) adducts positioned opposite cytosine, where 10S and 10R-trans-anti stereoisomers were positioned with opposite directionality in the minor groove without modified base-pair disruption. They also are in contrast to the 10S and 10R-cis-anti stereoisomers of (BP)G adducts opposite C, where the pyrenyl ring is intercalated into the helix with directionality, but the modified base and its partner on the opposite strand are displaced out of the helix. These results are especially significant given the known greater tumorigenic potential of fjord region compared to bay region polycyclic aromatic hydrocarbons. The tumorigenic potential has been linked to repair efficiency such that bay region adducts can be readily repaired while their fjord region counterparts are refractory to repair. Our structural results propose a link between DNA adduct conformation and repair-dependent mutagenic activity, which could ultimately translate into structure-dependent differences in tumorigenic activities. We propose that the fjord region minor groove-linked BPh-N-2-guanine and major groove-linked BPh-N-6-adenine adducts are refractory to repair based on our observations that the phenanthrenyl ring intercafates into the helix without modified base-pair disruption. The helix is thereforeminimally perturbed and the phenanthrenyl ring is not available for recognition by the repair machinery. By contrast, the bay region BP-N-2-G adductsare susceptible to repair, since the repair machinery can recognize eitherthe pyrenyl ring positioned in the minor groove for the trans-anti groove-aligned stereoisomers, or the disrupted modified basepair for the cis-anti base-displaced intercalated stereoisomers. (C) 2001 Academic Press.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 29/09/20 alle ore 10:32:26