About Careers MedBlog Contact us
Medindia LOGIN REGISTER
Advertisement

Key Enzyme in DNA Repair Pathway Disocvered

by Kathy Jones on July 31, 2010 at 9:33 PM
Font : A-A+

 Key Enzyme in DNA Repair Pathway Disocvered

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 has been identified by scientists.

Researchers at 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.

Advertisement

"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, 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.
Advertisement

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.

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.

Source: ANI
Advertisement

Advertisement
Advertisement

Recommended Reading

Latest Research News

Eight Threats to Black Adult's Longevity
Decoding the eight factors affecting Black adults' life expectancy.
Beyond the Campus: Contrasting Realities Revealed!
Sobering truth about foot travel in the United States emerges from international statistics, highlighting the prevalence of walking on the Blacksburg campus.
Astounding Link Between Darwin's Theory and Synaptic Plasticity  Discovered!
Unveiling a hidden mechanism, proteins within brain cells exhibit newfound abilities at synapses, reinforcing Darwin's theory of adaptation and diversity in the natural world.
Unlocking the Fountain of Youth: Exploring the Synergistic Power!
Combining micro-needling and cupping, two emerging and alternative techniques, in an experimental study reveals a potential synergy for skin rejuvenation.
Imminent Threat of the Next Pandemic - Disease X
Despite a decline in COVID-19 cases, the World Health Organisation (WHO) raises global concerns by warning of an "inevitable" next pandemic known as "Disease X".
View All
This site uses cookies to deliver our services.By using our site, you acknowledge that you have read and understand our Cookie Policy, Privacy Policy, and our Terms of Use  Ok, Got it. Close
×

Key Enzyme in DNA Repair Pathway Disocvered Personalised Printable Document (PDF)

Please complete this form and we'll send you a personalised information that is requested

You may use this for your own reference or forward it to your friends.

Please use the information prudently. If you are not a medical doctor please remember to consult your healthcare provider as this information is not a substitute for professional advice.

Name *

Email Address *

Country *

Areas of Interests