Cancer caused by DNA repair gone haywire

We don't know how to cure it, but now we've got a better idea what causes cancer. The disease starts when cells mess up their attempts to repair damage to their DNA.

There's a certain tragic irony to this, as these terrible diseases seem to begin with cells trying to fix the far more minor problem of damage to DNA strands. According to James Haber, Wade Hicks, and Minlee Kim of Brandeis University, cells that are showing the very earliest signs of cancer start to have errors in the DNA replication process. To fix this, the cells use a number or methods to repair the damage, one of which is known as gene conversion.

Gene conversion repairs the break in the DNA strand by using an almost identical sequence from elsewhere in the cell's DNA, providing a template from which the original strand can be reconstructed. Although this was once thought to be a mostly error-free process, the new study actually suggests it leads to a far greater number - about 1,400 times the usual amount - of DNA mutations than would otherwise be expected. Once these mutations affect the various genes that provide the cell's ability to control its own growth, the cell quickly becomes cancerous.

Coauthor James Haber says this theory explains why cells turn cancerous so quickly:

"It has been hard to imagine how cells could accumulate so many mutations in the few generations that they undergo cell division on the way to becoming cancerous. We think that the elevated rate of mutation at sites where DNA has been broken may be an important source of these gene changes."

Wade Hicks builds on this by noting that the mutations are themselves unique, and this could help test the validity of their ideas:

"During repair, mutation rates increase, and the types of mutation during repair are different from normal mutagenesis. It would be interesting to do an in depth analysis of the types of mutations in cancer cells and compare to those we observed in a repair event to see if they match up."

Their examination of gene conversion revealed that the copying of DNA during repair was often interrupted, which presented major complications. Most strikingly, the copying mechanisms would often choose the wrong template when they restarted, choosing an unhelpful sequence that provided little useful information for the strand in need of repair, which naturally created errors and mutations in the repair process. Gene conversion also fails to use another cellular repair system known as "mismatch repair", which is the only way the cell can notice and fix mutations that crop up. As such, gene conversion leaves all mutations in place, hastening their takeover of the cell's DNA.

The researchers say they will next focus on how often these template switches occur and what proteins are involved in the process. The hope is that this will better explain the runaway mutagenesis that leads to cancer and perhaps offer some clue as to how to prevent it from happening in the first place.