Project: Research project

Project Details


The broad long-term goal of this project is to understand how mutations
occur from the replication of carcinogen-modified DNA. The objective of
this grant proposal is to elucidate the interactions between DNA polymerase
and the minor groove of DNA. The specific aims are to determine which
sites in the minor groove of the DNA interact with the DNA polymerase
during replication. These interactions will be examined during the
replication of the normal DNA bases and theta6-methylguanine, a carcinogen-
modified base. Differences observed between correct and incorrect
replication will give clues as to the mechanisms that polymerases use to
replicate DNA with high fidelity. The health-relatedness of the project is
in carcinogenesis. Mutations that occur during replication of normal DNA
and carcinogen-modified DNA can lead to cancer. Understanding the
mechanism of the formation of mutations might alloW us to predict which
compounds are mutagens. The research design is to synthesize DNA analogs
in which sites in the minor groove are altered so that they can not
participate in hydrogen bonds. The kinetics of incorporation of modified
nucleotide triphosphates opposite modified DNA will be measured. Large
reduction in rates of replication will indicate that the altered site was
involved in a hydrogen bond with the polymerase.
Effective start/end date7/16/9712/31/07