Sci. Aging Knowl. Environ., 5 January 2005
Vol. 2005, Issue 1, p. nf2
[DOI: 10.1126/sageke.2005.1.nf2]

NEWS FOCUS

Mix and Mismatch

Cancer-promoting protein introduces mistakes in DNA pairing

Mitch Leslie

http://sageke.sciencemag.org/cgi/content/full/2005/1/nf2

DNA is as predictable as a bad sitcom--adenine lines up opposite thymine, and cytosine faces guanine. But occasionally nucleotides don't pair correctly, a flaw that can lead to cancer. A protein implicated in some tumors disrupts cells' ability to fix these errors, according to a new study. The work reveals a new function for the protein and might allow doctors to refine cancer treatments.

Several lines of evidence suggest that the protein Bcl-2 encourages cancer. For example, some types of tumors manufacture extra amounts of the protein. But researchers aren't sure how Bcl-2 abets rampant cell growth. The protein blocks apoptosis, or cellular suicide, suggesting one possible mechanism. Bcl-2 keeps cells with injured DNA alive, the argument goes. These cells can go on to form tumors when otherwise they would have killed themselves. Several recent studies indicate that Bcl-2 has another power: It perpetuates DNA damage by preventing cells from fixing errors. Youn and colleagues wanted to find out how Bcl-2 undermines DNA repair.

The team reared human cells engineered to produce varying quantities of Bcl-2. When the researchers added MNNG, a compound that damages DNA, cells that pumped out the most Bcl-2 were the most likely to survive. These cells also carried the most mutations, suggesting that Bcl-2 spares cells' lives but permits increased DNA damage. MNNG can trigger flaws known as mismatches, in which a nucleotide pairs with the wrong partner. Several enzymes team up to fix these errors, including one called hMSH2. Tests showed that cells that produced the largest quantities of Bcl-2 fashioned the least hMSH2. Moreover, the more Bcl-2 cells churned out, the worse they were at mending mismatches.

In addition to stymieing apoptosis, Bcl-2 halts cell division. To find out which capacity hampers mismatch repair, the scientists studied cells engineered to make one of two faulty types of the protein. One form prevents apoptosis but can't stop cell division. The other does the opposite. Cells unable to stop division fixed more mismatches than did apoptosis-inept cells. This finding suggests that terminating cellular reproduction helps quash DNA repair. That result seems paradoxical, the researchers note, because curtailing cell division usually protects against cancer. But by impeding mismatch repair, Bcl-2 might cause cells to amass mutations that could turn them cancerous late in life, the scientists speculate.

The paper "does a very good job of connecting the dots between Bcl-2 and the mismatch repair mechanism," says molecular biologist David Hockenbery of the Fred Hutchinson Cancer Research Center in Seattle, Washington. The result could pay off for patients, he says. Cancer-fighting treatments such as radiation and certain drugs increase mutations, and they might worsen cancers with extra Bcl-2 even though they kill other types of tumors. The work "shows that Bcl-2 can affect important cellular pathways besides its anti-apoptotic function to promote genomewide instability," says molecular oncologist Gary Vanasse of Yale University. The key question, he adds, is whether Bcl-2's effect on mismatch repair helps promote human cancers. Finding out might help researchers design treatments to keep DNA from straying from the formula.


January 5, 2005
  1. C.-K. Youn et al., Bcl-2 expression suppresses mismatch repair activity through inhibition of E2F transcriptional activity. Nat. Cell Biol., 26 December 2004 [e-pub ahead of print] doi:10.1038/ncb1215
Citation: M. Leslie, Mix and Mismatch. Sci. Aging Knowl. Environ. 2005 (1), nf2 (2005).








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