Harvard School of Public Health Boston, MA University of Texas Health Sciences Center San Antonio, TX Harvard Medical School Boston, MA
| Name | Organization | Role on Project |
|---|---|---|
| Leona Samson | Harvard School of Public Health | Project Leader |
| Tom Ellenberger | Harvard Medical School | Senior Investigator |
| Alan Tomkinson | Univ. Texas Health Sciences Center | Senior Investigator |
| Samuel Wilson | N.I.E.H.S., Research Triangle Park | Collaborator |
| Jeffrey Hansen | Univ. Texas Health Sciences Center | Collaborator |
The bases of DNA are continually damaged by environmental toxicants and reactive cellular metabolites. The repair of this damage is critical for the maintenance of our genomic integrity. The DNA glycosylases that initiate base excision repair (BER) locate damaged bases within a vast excess of normal DNA and initiate the removal of the chemically modified base. A growing body of experimental data indicates that DNA glycosylases hand off their abasic DNA product to the enzymes that catalyze subsequent steps of base excision repair. These protein-protein interactions during BER not only dictate the order, timing and progression of this repair pathway but also sequester potentially reactive and toxic reaction intermediates from other DNA metabolizing enzymes. In Project 1 of this proposal, we will exploit the complementary expertise of the Samson, Ellenberger and Tomkinson research groups to explore the molecular mechanisms that coordinate the multiple steps of BER. We will use a combination of biochemical,
Recent biochemical and genetic studies have revealed an unexpectedly
complex interplay between different cellular DNA repair pathways. Thus,
the study of different repair pathways within the Structural Biology of
DNA Repair (SDBR) program will produce synergistic interactions between
investigators with different expertise and enhance our understanding of
DNA repair in vivo. In particular, our studies of BER are
complementary to those of transcription-coupled BER and
replication-associated BER in Project 2. Since PCNA is required for
DNA mismatch repair and DNA synthesis associated with DNA double-strand
break, our proposed studies on the role of PCNA in BER will also be
relevant to Projects 3, 4 and 5.