Date of Award

1-1-2012

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Biomedical Sciences

Content Description

1 online resource (xvi, 233 pages) : illustrations (some color)

Dissertation/Thesis Chair

Joachim Jaeger

Committee Members

Janice D Pata, Nilesh Banavali, Joseph Wade, Thomas Begley

Keywords

crystallography, DNA repair, Polymerase ß, DNA polymerases, Mutation (Biology)

Subject Categories

Biochemistry | Biophysics

Abstract

DNA Polymerase ß (polß) plays a crucial role in repairing damaged DNA in a process called Base Excision Repair (BER). BER is a major pathway of DNA repair, making this system absolutely vital for maintaining genomic integrity. Recent studies estimate 30% of human tumors to contain polß variants that led us to believe that there is a high degree of association between mutations in polß and cancer. In this pathway, after recognition and excision of the damaged base, the DNA is cleaved at an apurinic (AP) site by AP endonuclease leaving behind a 3' hydroxyl and 5' deoxyribose phosphate (dRP). At this point, pol ß removes the dRP moiety and synthesizes short stretches of DNA to fill in the gap. While the magnesium- dependent nucleotidyl transferase activity is housed in the C-terminal 31 kD domain, the dRP lyase activity is localized in the smaller 8kD domain at the N-terminal end of pol ß. Unlike many of the larger replicative polymerases, pol ß does not have a proof reading activity. Therefore, if there is any compromise in pol ß gap-filling activity, it will result in the accumulation of gross sequence errors, which might lead to abnormal manifestations, including cancer. Interestingly, the corresponding mutations do not just map to the immediate active site of the polymerase domain (31K) but are also found a certain distance away from the catalytic center and the magnesium binding sites.

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