Environmental Factor, December 2006, National Institute of Environmental Health Sciences
LMG Speaker Peter Burgers on DNA Clamps
By Eddy Ball
An enthusiastic audience of research fellows gathered in Rodbell on October 30 to hear Peter M. J. Burgers, Ph.D., deliver the second talk in the Laboratory of Molecular Genetics (LMG) Special Seminars Series. Hosted by LMG Fellow Stephanie Nick McElhinny, Ph.D., the professor of Biochemistry and Biophysics at Washington University School of Medicine gave a talk titled "When Good DNA Turns Bad: Clamps Slide to the Rescue."
Burgers presented the latest results in his research group's investigations into the mechanisms of nuclear DNA replication and repair. The stability of an organism depends on its ability to maintain its DNA genome with a high degree of fidelity against the many accidental lesions that occur continually in DNA. DNA is subjected to stress and damage from heat shock, ultraviolet rays in sunlight, environmental exposures and metabolic processes. If an organism does not effectively replicate and repair DNA, cell mutation can occur with damaging and even life-threatening consequences.
Despite the thousands of random changes and "nicks" in DNA that occur daily, the repair process is so effective that only a few stable changes in DNA survive each year. Under normal conditions, a healthy organism is capable of quickly mounting emergency responses to severe DNA damage by synthesizing repair enzymes.
Burgers' talk focused on the role of two specialized DNA clamps in yeast that are associated with DNA repair. These clamps are donut-like protein assemblies that encircle double-stranded DNA and form organizing and stabilizing centers for enzymes that function in DNA metabolism. Burgers' laboratory has studied the proteins that participate with them in the repair process.
The first clamp Burgers discussed is involved in repairing damage at stalled replication forks in a process known as translesion DNA synthesis (TLS). His lab and others have identified a protein, Rev1, that interacts with ubiquinated proliferating cell nuclear antigen (PCNA) in order to initiate the TLS repair process. Studies have found that in vivo mutants in Rev1 interfere with TLS repair, indicating that Rev1 is essential for initiating the repair process.
The second clamp, the yeast PCNA-like checkpoint clamp, functions to halt the cell cycle in response to DNA damage. This interruption allows the organism to complete needed repairs prior to continuing the cell cycle to inhibit mutagenic development. Burgers' research team determined that a protein kinase, Mec1, forms a complex with the checkpoint clamp. Without the formation of the complex, necessary phosphorylation of downstream targets cannot take place, and the cell cycle will progress without repairs being made.
Understanding the clamp and clamp loading mechanisms in repair of DNA may ultimately offer insights into maintaining or restoring replication-competent complexes. This process is well conserved, and studies of DNA repair homologs in yeast and other lower organisms provide insight into the process in human cells.
Among the many honors he has received in the course of a career spanning 30 years, Burgers has been named an American Cancer Society Fellow and a Searle Scholarship Fellow. He has served of the editorial board of the Journal of Biological Chemistry, as well as a member of several NIH study sections. Burgers has contributed over 100 peer-reviewed articles to the medical literature and is the author of books and chapters on various aspects of biochemistry and biophysics.