Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers identify key enzyme in DNA repair pathway

30.07.2010
Protein complex helps cancer cells fight platinum-based drugs by fixing DNA cross-links

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 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 FA core complex containing eight FA proteins. These genes and proteins were discovered during research of Fanconi anemia, 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.

About MD Anderson

The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For seven of the past nine years, including 2010, MD Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News & World Report.

Laura Sussman | EurekAlert!
Further information:
http://www.mdanderson.org

More articles from Life Sciences:

nachricht Scientists discovered 20 new gnat species in Brazil
24.09.2018 | Estonian Research Council

nachricht Brought to light – chromobodies reveal changes in endogenous protein concentration in living cells
21.09.2018 | NMI Naturwissenschaftliches und Medizinisches Institut an der Universität Tübingen

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Scientists present new observations to understand the phase transition in quantum chromodynamics

The building blocks of matter in our universe were formed in the first 10 microseconds of its existence, according to the currently accepted scientific picture. After the Big Bang about 13.7 billion years ago, matter consisted mainly of quarks and gluons, two types of elementary particles whose interactions are governed by quantum chromodynamics (QCD), the theory of strong interaction. In the early universe, these particles moved (nearly) freely in a quark-gluon plasma.

This is a joint press release of University Muenster and Heidelberg as well as the GSI Helmholtzzentrum für Schwerionenforschung in Darmstadt.

Then, in a phase transition, they combined and formed hadrons, among them the building blocks of atomic nuclei, protons and neutrons. In the current issue of...

Im Focus: Patented nanostructure for solar cells: Rough optics, smooth surface

Thin-film solar cells made of crystalline silicon are inexpensive and achieve efficiencies of a good 14 percent. However, they could do even better if their shiny surfaces reflected less light. A team led by Prof. Christiane Becker from the Helmholtz-Zentrum Berlin (HZB) has now patented a sophisticated new solution to this problem.

"It is not enough simply to bring more light into the cell," says Christiane Becker. Such surface structures can even ultimately reduce the efficiency by...

Im Focus: New soft coral species discovered in Panama

A study in the journal Bulletin of Marine Science describes a new, blood-red species of octocoral found in Panama. The species in the genus Thesea was discovered in the threatened low-light reef environment on Hannibal Bank, 60 kilometers off mainland Pacific Panama, by researchers at the Smithsonian Tropical Research Institute in Panama (STRI) and the Centro de Investigación en Ciencias del Mar y Limnología (CIMAR) at the University of Costa Rica.

Scientists established the new species, Thesea dalioi, by comparing its physical traits, such as branch thickness and the bright red colony color, with the...

Im Focus: New devices based on rust could reduce excess heat in computers

Physicists explore long-distance information transmission in antiferromagnetic iron oxide

Scientists have succeeded in observing the first long-distance transfer of information in a magnetic group of materials known as antiferromagnets.

Im Focus: Finding Nemo's genes

An international team of researchers has mapped Nemo's genome

An international team of researchers has mapped Nemo's genome, providing the research community with an invaluable resource to decode the response of fish to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

"Boston calling": TU Berlin and the Weizenbaum Institute organize a conference in USA

21.09.2018 | Event News

One of the world’s most prominent strategic forums for global health held in Berlin in October 2018

03.09.2018 | Event News

4th Intelligent Materials - European Symposium on Intelligent Materials

27.08.2018 | Event News

 
Latest News

Matter falling into a black hole at 30 percent of the speed of light

24.09.2018 | Physics and Astronomy

NASA balloon mission captures electric blue clouds

24.09.2018 | Earth Sciences

New way to target advanced breast cancers

24.09.2018 | Health and Medicine

VideoLinks
Science & Research
Overview of more VideoLinks >>>