Study unveils structural details of enzyme vital to DNA repair

New findings may help development of potential cancer therapies

The findings suggest new strategies for targeting Mre11 protein for cancer therapies, particularly when combined with other inhibitors of DNA repair. Mre11 is a key component of cellular systems used for sensing, processing, and coordinating repair of two-stranded breaks in DNA. Mutations of this key enzyme can lead to the development of cancer.

The study was published in the October 3, 2008, issue (Volume 135, Number 7) of the journal Cell.

"Previous studies had suggested that Mre11 activity was not essential for initiation of homologous recombination repair—the critical pathway for error-free repair of DNA double-strand breaks," said John Tainer, a Scripps Research scientist and member of The Skaggs Institute for Chemical Biology, whose laboratory led the study with Scripps Research Professor Paul Russell. "Our work offers clear structural and biological evidence that Mre11 is central to the process, showing that Mre11 employs an endonuclease activity critical for initiation of recombination repair. This resolves paradoxes regarding the function of this nuclease, which has been recognized as the core components of the MRN complex, and gives us hope that we can target this key protein in cancer therapies."

Mre11 forms the core of the multifunctional Mre11-Rad50-Nbs1 (MRN) complex that detects DNA double-strand breaks, activates the ATM checkpoint kinase (which slows cell growth, giving the cell time to repair the breaks so that mutagenesis doesn't occur), and initiates homologous recombination repair of double-stranded breaks. Fission yeast, Schizosaccharomyces pombe, is often used as a model in cell cycle studies.

"The interesting thing about DNA repair biology," Tainer said, "is that cancer cells require intact DNA repair to maintain resistance to chemotherapies. The inhibition of recombination by targeting the Mre11 protein has significant promise for cancer therapeutics and could be combined with other inhibitors of DNA repair. Several studies in the past two years have reported mutations in MRN genes in several cancer types, especially colon and breast cancer."