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Contribution of DNA bending and open...

Seibert, Eleanore.

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Contribution of DNA bending and opening dynamics to the specific recognition of damaged DNA by repair enzymes.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Contribution of DNA bending and opening dynamics to the specific recognition of damaged DNA by repair enzymes./
Author:	Seibert, Eleanore.
Description:	188 p.
Notes:	Source: Dissertation Abstracts International, Volume: 63-12, Section: B, page: 5717.
Contained By:	Dissertation Abstracts International63-12B.
Subject:	Biophysics, General. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3075449
ISBN:	0493956042

Contribution of DNA bending and opening dynamics to the specific recognition of damaged DNA by repair enzymes.
Seibert, Eleanore.

Contribution of DNA bending and opening dynamics to the specific recognition of damaged DNA by repair enzymes. - 188 p.

Source: Dissertation Abstracts International, Volume: 63-12, Section: B, page: 5717.

Thesis (Ph.D.)--Mount Sinai School of Medicine of New York University, 2003.

A combination of experimental and theoretical methods has been utilized to study sequence-dependent efficiency of the base-excision repair enzyme, uracil DNA glycosylase (UDG). Previous reports indicated that DNA in complex with UDG is locally bent and the target uracil is flipped from the DNA helix. The work presented in this thesis addresses the hypothesis that local DNA structure and dynamics play a role in UDG efficiency. Specifically, sequences requiring less distortion energy will be better UDG substrates. Two model sequences containing A•U mismatches were selected based on previously reported results. Fluorescence spectroscopy using the adenine analogue, 2-aminopurine, and molecular dynamics simulations suggested sequence-dependent differences in bending flexibility for these two sequences. A full kinetic analysis of UDG activity for these sequences provided kinetic parameters and allowed the formulation of a relationship between local DNA bending flexibility and UDG activity. In an effort to extend the study to G•U mismatches, the fluorescent guanine analogue 6-methylisoxanthopterin (6MI) was characterized by spectroscopy and quantum chemistry. Subsequently, 6MI was incorporated opposite uracil in several sequence contexts to study sequence-dependent dynamics of these mismatches. Molecular dynamics simulations were used to compare the structure and dynamics of G•U and 6MI•U mismatches, and to characterize sequence-dependent bending and opening properties. Partial spontaneous base-pair opening is observed, and the relations of hydrogen bonding and base stacking to opening are discussed. Based on the results of the simulations and experiments, a model of specific recognition of damage by UDG is presented.

ISBN: 0493956042Subjects--Topical Terms:

1019105
Biophysics, General.

Contribution of DNA bending and opening dynamics to the specific recognition of damaged DNA by repair enzymes.
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500 $a Source: Dissertation Abstracts International, Volume: 63-12, Section: B, page: 5717.
500 $a Advisers: Roman Osman; J. B. A. Ross.
502 $a Thesis (Ph.D.)--Mount Sinai School of Medicine of New York University, 2003.
520 $a A combination of experimental and theoretical methods has been utilized to study sequence-dependent efficiency of the base-excision repair enzyme, uracil DNA glycosylase (UDG). Previous reports indicated that DNA in complex with UDG is locally bent and the target uracil is flipped from the DNA helix. The work presented in this thesis addresses the hypothesis that local DNA structure and dynamics play a role in UDG efficiency. Specifically, sequences requiring less distortion energy will be better UDG substrates. Two model sequences containing A•U mismatches were selected based on previously reported results. Fluorescence spectroscopy using the adenine analogue, 2-aminopurine, and molecular dynamics simulations suggested sequence-dependent differences in bending flexibility for these two sequences. A full kinetic analysis of UDG activity for these sequences provided kinetic parameters and allowed the formulation of a relationship between local DNA bending flexibility and UDG activity. In an effort to extend the study to G•U mismatches, the fluorescent guanine analogue 6-methylisoxanthopterin (6MI) was characterized by spectroscopy and quantum chemistry. Subsequently, 6MI was incorporated opposite uracil in several sequence contexts to study sequence-dependent dynamics of these mismatches. Molecular dynamics simulations were used to compare the structure and dynamics of G•U and 6MI•U mismatches, and to characterize sequence-dependent bending and opening properties. Partial spontaneous base-pair opening is observed, and the relations of hydrogen bonding and base stacking to opening are discussed. Based on the results of the simulations and experiments, a model of specific recognition of damage by UDG is presented.
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