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Researchers Identify Enzyme Involved in Chemotherapy Resistance Researchers at MD Anderson Cancer Center and at the Life Sciences Institute of Zhejiang University in China have discovered an enzyme that causes resistance to platinum-based chemotherapy drugs by helping cancer cells repair DNA damage. The discovery of the enzyme, called FAN1, and of its role in repairing DNA damage was recently reported in the Science Express advance online publication of the journal Science.
The platinum-based chemotherapy drugs cisplatin, carboplatin, and oxaliplatin work by causing cross-linking of the DNA strands in cancer cells, which blocks the cells’ ability to divide and leads to cell death. Although it has been known that the protein complex FANCI-FANCD2 responds to DNA damage and repairs cross-linking, the details of how the complex works were unknown. “This pathway that repairs cross-linking damage is a common factor in a variety of cancers, including breast cancer and especially ovarian cancer. If the pathway is active, it undoes the therapeutic effect of cisplatin and similar therapies,” said Junjie Chen, Ph.D., a professor in and chair of MD Anderson’s Department of Experimental Radiation Oncology and one of the report’s corresponding authors. “The breakthrough in this research is that we finally found an enzyme involved in this repair process.” In a series of experiments, the researchers demonstrated how the FANCIFANCD2 protein complex summons the FAN1 enzyme by acquiring a single ubiquitin molecule, connects with the enzyme by binding at the ubiquitin site, and moves the enzyme to the site of DNA cross-linking. They also showed that FAN1 cleaves branched DNA, which can result from DNA damage, but leaves the normal, double-stranded DNA alone. Mutant versions of FAN1 were unable to slice branched DNA. Dr. Chen said that analyzing the activity of this repair pathway could guide treatment with platinum-based agents, which could be administered when the cross-linking repair mechanism is less active. The FANCI-FANCD2 pathway is associated with the BRCA1 and BRCA2 pathways, Dr. Chen said. Mutations of the BRCA1 and BRCA2 genes are found in 5%–10% of women with ovarian and breast cancers.Visit www.mdanderson.org/newsroom for more information. Other articles in OncoLog, October 2010 issue:
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