Study unveils structural details of enzyme vital to DNA repair

Homologous recombination is a type of genetic recombination that involves the physical rearrangement and exchange of material between two strands of DNA. The process of homologous recombination occurs naturally, and is also utilized as a molecular biology laboratory technique for introducing genetic changes.

"Our study advances our understanding of how our cells handle DNA double-stranded breaks, whether the breaks are induced by exposure to environmental agents like radiation, or arise spontaneously due to errors in normal DNA metabolism," he said.

Cells balance DNA repair with DNA variation so that evolutionary or beneficial mutations can occur. In human cells, as many as 10,000 DNA bases are repaired each day, so these enzymes are essential to cell survival and protection against problematic mutations that may increase the risk of cancer.

New Structural Evidence

Using x-ray crystallography and small-angle x-ray scattering, the Scripps Research scientists were able to show precisely how these molecules bind to the DNA and how the core component of the complex—Mre11—is able to bridge the diverse molecular architectures found at DNA breaks.

"The structural evidence we uncovered provided us with molecular snapshots of the DNA binding event," said Russell. "When you break both strands of DNA, it's like breaking a piece of wood—you wind up with splintered ends with frayed tips. The Mre11 protein can not only recognize directly the broken ends of the DNA, it can also recognize those frayed ends with the overhanging DNA strands."

As a first responder to any double-stranded break, the MRN complex recruits the ATM checkpoint kinase, initiating a signaling cascade that leads to cell cycle arrest and checkpoint responses that are critical to maintaining the integrity of the human genome. Studies have shown that patients with mutations in the ATM gene are at much greater risk for cancer. But while the Mre11 complex subunits are essential for organism and cell viability in mammals, ATM is not; ATM activation is only one of the important Mre11 complex functions.

However, as the study noted, the Mre11 nuclease is found in every terrestrial organism on earth.