HOUSTON - Researchers have discovered an enzyme crucial to a type of DNA repair that also causes resistance to a class of cancer drugs most commonly used against ovarian cancer.
Scientists from The University of Texas MD Anderson Cancer Center and the Life Sciences Institute of Zhejiang University in China report the discovery of the enzyme and its role in repairing DNA damage called cross-linking in the Science Express advance online publication of Science.
"This pathway that repairs cross-linking damage is a common factor in a variety of cancers, including breast cancer and especially in ovarian cancer. If the pathway is active, it undoes the therapeutic effect of cisplatin and similar therapies," said co-corresponding author Junjie Chen, Ph.D., professor and chair of MD Anderson's Department of Experimental Radiation Oncology.
The platinum-based chemotherapies cisplatin, carboplatin and oxaliplatin work by causing DNA cross-linking in cancer cells, which blocks their ability to divide and leads to cell death. Cross-linking occurs when one of the two strands of DNA in a cell branches out and links to the other strand.
Cisplatin and similar drugs are often initially effective against ovarian cancer, Chen said, but over time the disease becomes resistant and progresses.
Scientists have known that the protein complex known as FANCI-FANCD2 responds to DNA damage and repairs cross-linking, but the details of how the complex works have been unknown. "The breakthrough in this research is that we finally found an enzyme involved in the repair process," Chen said.
The enzyme, which they named FAN1, appears to be a nuclease, which is capable of slicing through strands of DNA.
In a series of experiments, Chen and colleagues demonstrated how the protein complex summons FAN1, connects with the enzyme and moves it to the site of DNA cross-linking. They also showed that FAN1 cleaves branche
|Contact: Laura Sussman|
University of Texas M. D. Anderson Cancer Center