Molecular Tackle Halts Mutation

If faulty DNA were a grenade ready to explode into a genetic disease or birth defect, then researchers have now discovered the brave proteins that smother a ticking bomb to prevent it from damaging an organism. The findings, published in the 14 November Journal of Biological Chemistry, show that enzymes can prevent faulty DNA from being copied by latching onto corrupt regions.

Fragile DNA strands are constantly damaged by corrosive oxygen-based compounds and other byproducts of a cell's reactions, as well as by toxic molecules we eat or breath in. To keep the genetic code in order, enzyme bomb squads hustle up and down DNA strands, cutting out damaged sections with surgical precision. Other enzymes fill the gap by copying the healthy strand opposite the damaged one. If enzymes miss these scarred DNA regions, called lesions, the damage can get passed on as a mutation when the cell divides.

Now, a team from the Weizmann Institute of Science in Rehovot, Israel, has discovered a new way that this potential disaster is averted by two enzymes on the bomb squad: UvrA, an enzyme that recognizes DNA damage, and Fpg, which does part of the actual repair work. When the researchers added the copying enzyme DNA polymerase to a single DNA strand from Escherichia coli with a lesion in the middle of its nucleic acid sequence, the enzyme copied all the DNA, including the lesion. But with Fpg and UvrA added to the test tube, the polymerase copied only one-half of the DNA.

Since there was only one DNA strand and no healthy template, the enzymes could not perform their normal repair function. Instead, says team leader Zvi Livneh, the enzymes had recognized the lesion and clung to it, thereby blocking the polymerase from proceeding further down the strand. "These enzymes stall the replication process with their own bodies," he says.

The experiment "quite clearly and convincingly demonstrates that this is a new mechanism to prevent mutations," says Jan Hoeijmakers, a molecular biologist who studies DNA repair at Erasmus University in Rotterdam, The Netherlands. Hoeijmakers says it's likely that human cells use similar roadblocks to prevent defective DNA from duplicating, since DNA repair systems are almost identical in all living organisms.