The broad, long-term objective of this project is to attain an in-depth understanding of the molecular-structural basis of DNA/RNA polymerase catalytic activity and function. To this end the project will focus on the DNA polymerase beta of both human and rat, primarily using the technique of X-ray crystallography to visualize, at atomic resolution, the molecular structures of complexes in which the enzyme is bound to a range of synthetic DNA template-primer segments and nucleoside triphosphate monomers. Vertebrate DNA polymerase beta provides an excellent target for such studies as it is the smallest and functionally simplest of polymerases, but one which nevertheless bears an obvious family resemblance to the polymerase domains of larger, more complex enzymes. Template directed polymerization of RNA/DNA, in other words the polymerase reaction, is the most fundamental of biological processes. It is essential to cellular maintenance and replication. The cellular role of polymerase beta in particular is repair of a common type genomic error, which results in short gaps in one DNA strand that must be filled in by this enzyme. Accumulated errors in DNA, that is accumulated somatic mutations, are according to one widely accepted working hypothesis the root cause of most cancers and perhaps even of the aging process. A basic understanding of polymerase action in molecular terms, therefore, could conceivably lead some day to techniques for slowing the somatic mutation rate, with profoundly beneficial medical consequences.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM052860-01
Application #
2192046
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Project Start
1995-08-01
Project End
1999-07-31
Budget Start
1995-08-01
Budget End
1996-07-31
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093