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Dissertation Information for Julie McClure Villanueva

NAME:
- Julie McClure Villanueva

DEGREE:
- Ph.D.

DISCIPLINE:
- Chemistry

SCHOOL:
- Emory University (USA) (1999)

ADVISORS:
- Luigi G. Marzilli

COMMITTEE MEMBERS:
- Karl S. Hagen
- Craig L. Hill

MPACT Status: Fully Complete

Title: Chemical modifications of DNA

Abstract: "Using CD and UV-vis spectroscopy and viscometric methods, T[Special characters omitted.] F 4 TAP ( meso -tetrakis[2,3,5,6-tetrafluoro-4-(2-trimethylammoniumeth[Special characters omitted.] ylamine)phenyl]porphyrin) binds to CT DNA, [poly(dA-dT)] 2 , and [poly(dG-dC)] 2 in a self-stacking, outside-binding manner, preferentially binding to [poly(dA-dT)] 2 over [poly(dG-dC)] 2 ; thus, T[Special characters omitted.] F 4 TAP binding is affected by base pair composition. T[Special characters omitted.] F 4 TAP is the first electron deficient porphyrin with shape similar to intercalating porphyrins that does not intercalate.

Using electrophoretic methods, G3-D (d(A 1 [Special characters omitted.] T 2 [Special characters omitted.] G 3 [Special characters omitted.] G 4 [Special characters omitted.] G 5 [Special characters omitted.] T 6 [Special characters omitted.] A 7 [Special characters omitted.] C 8 [Special characters omitted.] C 9 [Special characters omitted.] C 10 [Special characters omitted.] A 11 [Special characters omitted.] T 12 )) and G3-H (d(A 1 [Special characters omitted.] T 2 [Special characters omitted.] G 3 [Special characters omitted.] G 4 [Special characters omitted.] G 5 [Special characters omitted.] T 6 [Special characters omitted.] T 7 [Special characters omitted.] C 8 [Special characters omitted.] C 9 [Special characters omitted.] C 10 [Special characters omitted.] A 11 [Special characters omitted.] T 12 )) form G 4 N7-mono-adducts with cisplatin ( cis -Pt(NH 3 ) 2 Cl 2 ), which undergo 3 ' -chelation, affording mostly the G 4 ,G 5 intrastrand N7-Pt-N7 adduct ([Special characters omitted.] 96% G3-D , [Special characters omitted.] 70% G3-H ). NMR data indicated that G3-H has a B-form stem and a non-helical loop. Zn 2+ or Mg 2+ ions transformed G3-H into a bulged duplex. The cross-linked adduct ratio is insensitive to DNA form or Pt leaving group for G3-H . For G3-D , this ratio is much lower in the cis -[Pt(NH 3 ) 2 (H 2 O) 2 ] 2+ reaction than in the cisplatin reaction, indicating that the leaving group influences the cross-linking step. Regardless of conformation, 3 ' -direction cross-linking is favored at telomeric GGGT sequences, suggesting that the sequence itself contributes cross-linking preference. The [( R , S , S , R )- Bip Pt(H 2 O) 2 ] 2+ - G3-D ( Bip = 2, 2 ' -bipiperidine) reaction resulted in the G 3 ,G 4 cross-linked adduct only from the G 3 - and G 4 -mono-adducts; thus, altering the carrier and leaving ligands can completely change which adduct is preferred. G3-D formed G 3 ,G 4 and G 4 ,G 5 cross-linked adducts with [( S , R , R , S )-BipPt(H 2 O) 2 ] 2+ in a [Special characters omitted.] 40:60 ratio from the G 4 -mono-adduct. The chirality of the Bip ligand has a decisive influence on the cross-linking process and the initial reaction with G3-D . While cis -Pt(NH 3 ) 2 - G3-D adducts disfavor duplex formation, the Bip Pt- G3-D adducts primarily formed duplexes. More than one conformer of the Bip Pt- G3-D adducts were observed.

Using NMR methods, (d(C 1 G 2 C 3 G 4 A 5 C 6 A 7 T 8 G 9 T 10 DHU 11 G 12 C 13 [Special characters omitted.] G 14 )) DHU-14 , DHU = 5,6-dihydrouracil) was a B-form duplex with intrahelical G 4 -DHU 11 wobble base-pairs, all bases in the anti -conformation, and all sugars with S pucker. Nth recognizes and cleaves DHU and thymine glycol (Tg), which is extrahelical, forming distorted duplexes. Therefore, a large structural change in B-DNA is not the signal for Nth repair. Nth enzymes probably recognize the presence of nonplanar, saturated bases, regardless of helicity."

MPACT Scores for Julie McClure Villanueva

A = 0
C = 0
A+C = 0
T = 0
G = 0
W = 0
TD = 0
TA = 0
calculated 2008-04-13 14:12:00

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