Protein Averts Cell Suicide but Might Contribute to Cancer
Scientists have discovered how an unusual protein helps a cell bypass damage when making new DNA, thereby averting the cell's self-destruction. But they also discovered that this protein, an enzyme called Dpo4, often makes errors when copying the genomic DNA sequence that later might cause the cell to become cancerous.
The findings by researchers with Ohio State University's Comprehensive Cancer Center are described in two back-to-back papers in the March 16 issue of The Journal of Biological Chemistry.
"Unrepaired DNA damage presents a big roadblock for the DNA replication machinery, which cannot go around it," says Zucai Suo, assistant professor of biochemistry. "This damage will trigger cell death because the DNA is not replicated.
"This protein bypasses the damage and saves cells from self-destructing, but it is very error prone, which suggests that it may also play a role in cancer."
Dpo4 is one of a family of enzymes called Y-family DNA polymerases that were first discovered about 10 years ago and are only now becoming understood.
"These enzymes provide a survival mechanism for cells," says first author Kevin Fiala, a graduate student in Suo's laboratory. "They allow DNA replication to continue, so the cell doesn't die. But they don't repair the DNA damage that exists."
DNA damage is a routine problem for cells, Suo says. For example, every cell loses more than 10,000 DNA bases daily. Dedicated repair enzymes fix 80 percent or more of this damage, but the rest remains.
Cells use Y-family enzymes to bypass that remaining damage when making new DNA prior to cell division, thus forcing these enzymes to copy damaged DNA.
How these bypass enzymes work, however, isn't known. The Dpo4 protein used in this research comes from a microorganism. It is relatively easy to produce in large quantities and to study, and it is similar to one of the four such enzymes found in humans.
For this research, Fiala developed a new way to sequence very short lengths of DNA. "This allowed us to pin down exactly what mistakes Dpo4 makes," he says.
The findings reveal why the enzyme makes mistakes.
DNA resembles a spiral staircase that is made from separate halves, with half-steps protruding from each. The half-steps fit together down the center to form the complete staircase.
In DNA, the half-steps are known as the bases