p53 Protein Broken? Break It Again

A genetic mutation usually leads to crippled and misfolded proteins, but in rare instances an additional mutation can bring a protein back to life. Now researchers have discovered a mutation that fixes a key protein that's often broken in cancer cells. The find, reported in this week's issue of the European Molecular Biology Organization Journal, could eventually lead to the development of new drugs that shore-up misfolded proteins.

In healthy human cells, the p53 protein helps prevent tumors by putting the brakes on the cell cycle to give an ailing cell time to fix itself--or die--rather than spawning more corrupted cells. In many cancerous cells, p53 doesn't work because the gene coding for it has mutated. Hoping to patch up the protein, researchers at Johns Hopkins University in Baltimore, Maryland, and Memorial Sloan-Kettering Cancer Center in New York City, took mutated p53 genes and introduced additional random mutations by a process called PCR mutagenesis.

To see if any of the doubly flawed genes would make working proteins, the researchers inserted them into yeast cells engineered to not grow unless a functioning p53 protein was present. "This is a yeast that lives or dies by human p53 activity," says Johns Hopkins yeast geneticist Jef Boeke. Most "just sat there," Boeke says. But out of millions of mutations, a handful allowed the yeast cells to flourish. The researchers put the twice-mutated p53 genes back into human cells and found that they worked there too.

Boeke says the second mutation could be compensating for the first one by helping the mutated p53 protein fold more like the normal version. "Interesting," muses p53 pioneer Arnold Levine of Princeton University, but "the really powerful thing will be to identify the structure" of the doubly mutated protein. Then, he says, it might be possible to create a drug that would twist mutated proteins into a shape that works.

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