Date of Award

2000

Document Type

Honors Thesis (Open Access)

Department

Colby College. Chemistry Dept.

Advisor(s)

Julie T. Millard

Second Advisor

Paul G. Greenwood

Third Advisor

Shari U. Dunham

Abstract

DNA interstrand cross-linking agents have been recognized for many years to be powerful antitumor chemotherapeutics. While the interactions between free DNA and many anticancer drugs have been explored extensively, there is less infonnation available about these interactions with nucleosomal DNA. Nitrogen mustards have been reported to exhibit relatively similar cross-linking sites and efficiencies of binding in free and nucleosomal DNA, but mitomycin C exhibits markedly reduced cross-linking near the center of nucleosomal DNA. This current study focuses on cisplatin interstrand cross-linking of the 154 base pair 55 rRNA gene fragment of Xenopus borealis reconstituted with histones from chicken erythrocytes. The results showed that nucleosomal structure positively affects the efficiency of interstrand cross-linking of DNA by cisplatin at one site on the gene, believed to be at a site three-helical turns from the dyad. Nevertheless. nuc1eosomal structure does not determine the sites at which cisplatin can bind to DNA. The similarity in cross-linking patterns between free and nucleosomal DNA supports a locally dynamic model of the nucleosome. Additional reconstitution experiments also demonstrate that a cisplatin-modified DNA molecule cannot be precisely incorporated into a nucleosome, indicating that cross-linking of the DNA molecule somehow impedes adoption of nucleosomal structure.

Keywords

DNA cross-linking agents, antitumor chemotherapeutics, interaction, nucleosomal DNA, cisplatin interstrand cross-linking, Xenopus borealis

Download

Included in

Chemistry Commons

Share

COinS