Mutated forms of p53 gene and proteins Chk1 and Chk2 in fruit flies results in insufficient apoptosis, according to Genetics article.

University of Utah biologists working with fruit flies have discovered how cells avoid apoptosis even when telomere loss occurs. They say that mutated forms of checkpoint proteins Chk1 and Chk2 along with already implicated mutated p53 are necessary to halt the normal apoptosis process in cells.


They also noticed that a nonmutant cell lacking a telomere occasionally escapes suicide and divides. Then its progeny accumulate defects including the wrong number of chromosomes or chromosomes that have exchanged pieces with each other. Those defects are hallmarks of cancer cells.


Previous research has shown that aging and cancer often are associated with loss or shortening of telomeres. This study shows that losing just one telomere can lead to abnormalities in a cell’s chromosomes.


A possible reason a cell avoids suicide even after telomere loss and other damage is that chromosomes in the cell’s offspring regain telomeres, according to the researchers. They say all cancer cells have figured out how to add new telomeres, which allows them to survive and divide indefinitely.


In their study, the investigators triggered telomere loss by inserting into the flies a gene from common baker’s yeast. The gene makes an enzyme that breaks and rejoins DNA. When they turned on the enzyme, it led to the loss of a single telomere in each affected fruit fly cell. As expected most of these cells died.


Next, they repeated the experiment using flies in which p53, Chk1, or Chk2 were mutated. Destroying the cell apoptosis genes and then damaging the chromosomes allowed more damaged chromosomes to survive instead of committing suicide.
In a normal fly, when a telomere is lost, only 10% to 20% of cells with such damage survive, with the rest killing themselves. But in flies whose suicide genes were crippled, up to 75% of cells survived despite lacking a telomere.


The scientists did find another way cells can commit suicide if they avoid that fate due to p53, Chk1, or Chk2 damage. This occurs when the damaged cell divides and its progeny have the wrong number of chromosomes. The resulting genetic imbalance can cause cell suicide. Telomere loss also is linked to this alternative form of cell suicide. The study shows for the first time that this type of cell death which doesn’t use p53 is caused by gaining or losing copies of other important genes.


The study will be published in the December issue of the Genetics.


 

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