Published in today’s issue of Molecular Cell, their paper entitled “A RAP1/TRF2 Complex Inhibits Non-Homologous End Joining at Human Telomeric DNA Ends” employed a biochemical assay for double-strand break repair to define the minimal requirements for the protection of telomeric DNA at the ends of chromosomes.
“Surprisingly, we found that neither long single-stranded overhangs nor t-loop formation is essential to prevent illegitimate repair of telomeric ends,” said Dr. Bae. “Instead, a short tandem array of telomeric repeats bound by a Rap1/Trf2 complex is sufficient to impede non-homologous end joining in a highly directional manner.”
It has long been understood that chromosome ends are distinct from DNA double-strand breaks and that the cellular machinery that repairs DNA breaks does not act on telomeres. But how repair factors are prevented from acting at chromosome ends has been a hotly debated issue. Over the past decade, several telomeric complexes and structures have been identified and proposed to protect chromosome ends, but conclusive evidence that any of these are required for protection has been lacking.
“We set out to define the minimal requirements that would allow the DNA repair machinery to distinguish a chromosome end from a break,” said Dr. Baumann. “By establishing an in vitro assay for chromosome end protection and by implicating specific proteins, we have opened the door to elucidate the mechanism by which RAP1/TRF2 inhibits double-strand break repair at chromosome ends.”
“These findings are important for establishing a better understanding of tumor development,” said Robb Krumlauf, Ph.D., Scientific Director. “Genomic instability and gross chromosomal rearrangements are a hallmark of cancer cells. The mechanisms that initiate and drive these events are only poorly understood, but it is widely accepted that loss of chromosome end protection can initiate genomic instability through bridge-breakage-fusion cycles. It is, therefore, very important to understand the mechanism of chromsome end protection and how and why it fails during tumorigenesis.”
Dr. Baumann, who received a Pew Scholar Award in 2003 and a Basil O’Connor Scholar Award in 2004, holds an academic appointment as an Assistant Professor in the Department of Biochemistry & Molecular Biology at The University of Kansas School of Medicine. To learn more about the work of the Baumann Lab, visit http://www.stowers-institute.org/labs/BaumannLab.asp.
About the Stowers Institute
Housed in a 600,000 square-foot state-of-the-art facility on a 10-acre campus in the heart of Kansas City, Missouri, the Stowers Institute for Medical Research conducts basic research on fundamental processes of cellular life. Through its commitment to collaborative research and the use of cutting-edge technology, the Institute seeks more effective means of preventing and curing disease. The Institute was founded by Jim and Virginia Stowers, two cancer survivors who have created combined endowments of $2 billion in support of basic research of the highest quality.
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