City of Hope scientists have found a key to a protein’s ability to repair and make new copies of DNA. The study, published online Aug. 22 in Nature Chemical Biology, opens further understanding of how cancer may develop.
Led by Binghui Shen, Ph.D., professor and associate chair of the Department of Cancer Biology in Beckman Research Institute of City of Hope, the researchers found a new way that cells modify a protein called flap endonuclease 1, or FEN1, to control its activity.
|Binghui Shen studies DNA repair mechanisms. (Photo by Paula Myers)|
FEN1 plays important roles in proper DNA duplication, repair and clean up — all critical to keeping cells healthy.
“Because it serves multiple purposes, FEN1 must be carefully controlled so that it performs the right job at the right time and place in the cell,” Shen said.
In the study, Shen’s team tried to understand how cells guide FEN1 to where it is needed.
Cells replicate DNA to make duplicate copies of chromosomes before dividing to form two new cells. The process is complicated, and if errors arise in the DNA, cells may die — or worse, become cancerous. Damage in existing DNA that goes unrepaired can lead to disease, as well.
FEN1 helps guarantee error-free DNA replication and repair.
The researchers found that a chemical modification called methylation is key to ensuring that FEN1 can travel to replicating DNA to do its job. When a protein is methylated, it carries small chemical “knobs,” called methyl groups, at particular points on its structure.
Shen and his team found that FEN1 must be methylated to link up with another protein, which then carries it to the site of active DNA replication. Once there, FEN1 ensures replication goes smoothly.
The same process also carries FEN1 to certain DNA damage sites, where it aids repair.
When the researchers prevented FEN1 methylation, however, the protein underwent a different chemical modification that kept it from going where it was needed. That can spell trouble.
“In cells where FEN1 methylation was blocked, we saw a much higher frequency of mutations in the genome,” Shen said. This makes the chromosomes unstable and can lead the cells to turn cancerous, he explained.
The researchers are delving further into the mechanisms involved, hoping to better understand how cells move FEN1 around and what mishaps may arise to prevent methylation and lead to cancer.
City of Hope researchers on the study include Zhigang Guo, Ph.D., Li Zheng, Ph.D., Hong Xu, Huifang Dai, Mian Zhou, M.D., Ph.D., and Mary Rose Pascua. Qin M. Chen, Ph.D., of the University of Arizona also contributed to the research. The study was supported by grants from the National Cancer Institute.