Scientists investigating an important DNA-repair enzyme now have a better picture of the final steps of a process that glues together, or ligates, the ends of DNA strands to restore the double helix.
The enzyme, DNA ligase, repairs the millions of DNA breaks generated during the normal course of a cell's life, for example, linking together the abundant DNA fragments formed during replication of the genetic material in dividing cells.
"Our study shows that DNA ligase switches from an open, extended shape to a closed, circular shape as it joins DNA strands together," says the study's senior author Tom Ellenberger, D.V.M, Ph.D., the Raymond H. Wittcoff Professor and head of the Department of Biochemistry and Molecular Biophysics at Washington University School of Medicine in St. Louis. "The ligase resembles a wristwatch that latches around the DNA ends that are being joined."
DNA is surprisingly reactive and under continuous assault from environmental toxins and reactive cellular metabolites. A means of repairing DNA damage is vital to maintaining the integrity of the genetic blueprint.
When these repair processes go awry, cells can malfunction, die or become cancerous, so researchers would like to know how "DNA mechanics" do their jobs. DNA ligases are attractive targets for the chemotherapy of cancer and other diseases.
DNA ligase works in concert with another ring-shaped protein known as a sliding clamp. Sliding clamps, such as the human PCNA protein, are master regulators of DNA repair, providing docking sites that recruit repair enzymes to the site of damage.
"When ligase stacks against PCNA and encircles the DNA, we think this interaction ejects other repair proteins from PCNA," says Ellenberger. "In this role, ligase may serve as the final arbiter of DNA repair, certifying that the DNA is in pristine condition and ready for the final step of DNA end joining."
In this study of DNA ligase, published in the Oct. 20 issue
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Contact: Gwen Ericson
ericsong@wustl.edu
314-286-0141
Washington University School of Medicine
19-Oct-2006