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The Scripps Research Institute
Overexpression of the cyclin E protein may cause leukemia and breast cancer, according to research published in Current Biology.
The study suggested that overexpression of cyclin E slows down DNA replication and introduces potentially harmful oncogenic mutations when cells divide.
“Overexpression of cyclin E is one route to cancer,” said study author Steven Reed, PhD, of The Scripps Research Institute in La Jolla, California.
Dr Reed and his colleagues originally discovered cyclin E, and their previous studies showed that abnormally high levels of cyclin E are associated with chromosome instability, increasing the chances that a chromosome will acquire more mutations as it divides.
The researchers found that cyclin E is frequently overexpressed in cancer cells, and that overexpression is linked to a decreased survival rate for breast cancer patients.
However, until they conducted the current study, the team didn’t know exactly how cyclin E introduces chromosome instability and errors into DNA.
DNA ‘tug-of-war’
The researchers investigated the role of cyclin E by comparing normal human mammary cells with mammary cells forced to overexpress cyclin E at the same levels seen in some breast cancer cells.
They found that DNA replication took significantly longer in the cyclin E-deregulated cells. In fact, the cells seemed to enter the next stage of cell division before the DNA was even done replicating. A small number (n=16) of very specific regions on the chromosomes frequently failed to complete replication.
The researchers then screened the cyclin E-deregulated cells for errors later in the cell division process. And they found that chromosomes of the deregulated cells’ daughter cells stuck together in the spots where replication had not finished.
“You could see a tug-of-war going on,” Dr Reed said. “That would cause either the chromosome to tear or both chromosomes to go to one side.”
The researchers spotted abnormal DNA “bridges” tying daughter cells together, as well as cells in which chunks of chromosomes ripped away and floated nearby. After these abnormal divisions took place, a third of the cyclin E-deregulated cells showed DNA deletions at the previously identified regions where replication failed.
The link to cancers
Next, the researchers investigated how the genetic instability from DNA deletions in cyclin E-deregulated cells could contribute to cancer. Many of the sites with DNA deletions were areas in which DNA was already known to be fragile or difficult to replicate.
Using a database of tumor DNA sequences, the team found that 6 of the 16 DNA regions they had identified in their cell-based studies showed damage in breast tumors that could be directly linked to cyclin E overexpression.
In addition, an area commonly damaged in cyclin E-deregulated cells matched up with an area commonly rearranged in mixed-lineage leukemia, where cyclin E had already been shown to be a contributing factor.
One of the unanswered questions posed by this work is how cells are allowed to divide before all the chromosomes are completely replicated. It was believed that “checkpoints” exist to prevent this from happening.
Dr Reed thinks these unreplicated regions are small enough to bypass the cellular checkpoints and keep cells dividing and accumulating potentially harmful mutations.
His team’s next step is to sequence the entire genomes of cells that undergo damage from cyclin E overexpression to understand exactly how the deletions contribute to cancer.
