Researchers Identify “Missing Link” Underlying DNA Repair & Platinum Drug Resistance

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.

Junjie Chen, Ph.D., Professor and Chair, Department of Experimental Radiation Oncology, University of Texas M.D. Anderson Cancer Center

“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 such as 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 FANCIFANCD2 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 branched DNA but leaves the normal, separate double-stranded DNA alone. Mutant versions of FAN1 were unable to slice branched DNA.

Like a lock and key

The researchers also demonstrated that FAN1 cannot get at DNA damage without being taken there by the FANCI-FANCD2 protein complex, which detects and moves to the damaged site. The complex recruits the FAN1 enzyme by acquiring a single ubiquitin molecule. FAN1 connects with the complex by binding to the ubiquitin site.

“It’s like a lock and key system, once they fit, FAN1 is recruited,” Chen said.

Analyzing the activity of this repair pathway could guide treatment for cancer patients, Chen said, with the platinum-based therapies used when the cross-linking repair mechanism is less active.

Scientists had shown previously that DNA repair was much less efficient when FANCI and FANCD2 lack the single ubiquitin. DNA response and damage-repair proteins can be recruited to damage sites by the proteins’ ubiquitin-binding domains. The team first identified a protein that had both a ubiquitin-binding domain and a known nuclease domain. When they treated cells with mitomycin C, which promotes DNA cross-linking, that protein, then known as KIAA1018, gathered at damage sites. This led them to the functional experiments that established its role in DNA repair.

They renamed the protein FAN1, short for Fanconi anemia-associated nuclease 1. The FANCI-FANCD2 complex is ubiquitinated by an Fanconi anemia (FA) core complex containing eight FA proteins. These genes and proteins were discovered during research of FA, a rare disease caused by mutations in 13 fanc genes that is characterized by congenital malformations, bone marrow failure, cancer and hypersensitivity to DNA cross-linking agents.

Chen said the FANCI-FANCD2 pathway also is associated with the BRCA1 and BRCA2 pathways, which are involved in homologous recombination repair. Scientists know that homologous recombination repair is also required for the repair of DNA cross-links, but the exact details remain to be resolved, Chen said. Mutations to BRCA1 and BRCA2 are known to raise a woman’s risk for ovarian and breast cancers and are found in about 5-10 percent of women with either disease.

Co-authors with Chen are co-first author Gargi Ghosal, Ph.D., and Jingsong Yuan, Ph.D., also of Experimental Radiation Oncology at MD Anderson; and co-corresponding author Jun Huang, Ph.D., co-first author Ting Liu, Ph.D., of the Life Sciences Institute of Zhejiang University in Hangzhou, China.

This research was funded by a grant from the U.S. National Institutes of Health and the Startup Fund at Zhejiang University.

Sources:

2 thoughts on “Researchers Identify “Missing Link” Underlying DNA Repair & Platinum Drug Resistance

  1. OK, so what now? the research has found a possible target in the fight against ovarian cancer. Will anyone now use this information to actually devise a therapy? Seems as though all we ever hear about are the results of someone’s research, then nothing follows.

    gh

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    • Hi Gene,

      I really do like a general atmosphere of skepticism when it comes to medical research; however, I think that you may have “thrown out the baby with the bathwater,” given your broad, sweeping generalization. You, like all of us, get frustrated with the “slow” pace of ovarian cancer drug development. I will grant you that. But, we would be remiss if we did not point out a few basic facts. First, basic science by definition must come before drug development. In my opinion, we did not really begin to solve the cancer issue until 2000, when scientists completed the Humane Genome Project. Next, they will be working on the Human Epigenome. After that, scientists must turn to the inner working of the cell down to the molecular level. That’s a yeoman’s job to say the least.

      As you well know, discoveries do not result from all basic science. In fact, if scientist are truly performing cutting-edge work, you should expect many dead ends. Without risk, there is no reward. Once a discovery is made, and assuming a therapeutic drug target is identified, you need biomarkers to determine who will benefit the most from the preclinical drug or compound. Next, you need to run clinical trials to identify those biomarkers and determine the safety and efficacy of the investigated drug. On average, a U.S. FDA-approved drug can take 7 years and $1 billion to develop. And, to add insult to injury, the U.S., for example, only spends 69 cents per person, per week, on all private and public cancer research. We spend more money on soda each week than we do on cancer research!

      Needless to say, there are many reasons underlying the general frustration that you note in your comment. But, there is good work being done in the area of ovarian cancer. Yesterday, I posted an article entitled, Largest Study Matching Genomes To Potential Anticancer Treatments Releases Initial Results. This is a great example of cutting-edge research directly aimed at the identification of “personalized” ovarian cancer therapies based upon specific human genomes. This is clearly a case of working smarter, not harder. If you click on the “Novel Therapies” category located on the website homepage left sidebar, you will find many examples of basic science that turned into clinical investigation drugs.

      Additional open issues with drug development include: (i) getting competing pharmaceutical/biotechnology companies to combine two or more drugs for clinical study, and (ii) making the general public more aware of the benefits associated with clinical study participation. The latter issue is big considering the following: 85% of the public has an interest in clinical trials, but only 9% of those individuals discuss the issue with their doctor, and out of those, only 3% actually participate. If you want to speed drug development, we need to significantly increase the number of clinical trial participants. This obstacle can be problematic with ovarian cancer due to the fact that in the U.S., there are only 176,000 women alive at any given time who are affected by ovarian cancer (i.e., either in treatment or remission). In contrast, there are over 100 ovarian cancer drugs in clinical development. If you do the math, you will find that there simply are not enough women to fill all of the open clinical trials.

      A partial answer to the problem above is to pursue a course similar to that being taken by the Massachusetts General Hospital Cancer Center and the Wellcome Trust Sanger Institute. We need to identify common genetic defects present in a large population of ovarian cancer patients, and conduct clinical trials to test drugs or preclinical compounds against those defects. This process seems to be efficient given the limited number of women available to participate in clinical trials.

      Gene, I applaud your frustration, because without it, progress will not be made. However, on a global basis, we need to (i) increase cancer research spending, (ii) make the public better aware of clinical trial benefits, and (iii) design more drugs/compounds to use in those trials. In the U.S., Massachusetts General Hospital and the M.D. Anderson Cancer Center are performing limited genetic testing on tumor biopsies, for the purpose of directing patients to potentially beneficial clinical trials based on the uniqueness of their particular type (or subtype) of cancer.

      I hope this discussion helps you to better understand the difficult issues relating to current drug development. Best regards, Paul

      Like

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