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Ludwig scientist discovers key mechanism in DNA repair

DNA mismatch repair (MMR) is the body’s system for recognizing and fixing mispaired bases (adenine with thymine, guanine with cytosine) that occur during genetic replication and recombination. It’s a vital process because it eliminates mutations that can result in defects and the development of different cancers.

It’s also a bit of a mystery, in part because no one has ever actually seen the system at work. Until now. In a paper published in the November 23 issue of the journal Cell, Richard Kolodner, PhD, a member of the Ludwig Institute for Cancer Research, professor of medicine and member of the Moores Cancer Center at UC San Diego School of Medicine and colleagues use fluorescent visualization techniques to show what’s happening in vivo for the first time.

The researchers studied live cells of Saccharomyces cerevisiae, a species of yeast. “MMR in yeast and humans is exactly the same,” said Kolodner. “Yeast and humans use the same proteins and the repair process involves the same steps in each organism.”

They focused on the Msh2-Msh6 and Mlh1-Pms1 protein complexes, known to play a role in MMR. “We saw that the MMR protein that detects errors in the DNA linked to the proteins that replicate the DNA,” said Kolodner. “We also saw that when the first MMR protein encountered an error in the DNA, it assembled a second MMR protein onto the DNA to initiate the repair process.”

The discovery reveals for the first time a key mechanism used by MMR proteins to find individual damaged sites in DNA among the vast numbers of non-damaged DNA sites in a cell. Having a better understanding of how DNA is repaired could ultimately lead to future therapies to assist the process or treat existing cancers.

“Inherited defects in MMR genes cause one of the most common forms of inherited cancer susceptibility known,” said Kolodner. “In addition, a significant number of non-inherited cancers have MMR defects that play a role in their development. And sometimes in cancers that have become resistant to chemotherapy, the acquired resistance is due to selection for a MMR defect during treatment.”

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