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Researchers identify key enzyme in DNA repair pathway
Date:7/29/2010

d 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
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Contact: Laura Sussman
lsussman@mdanderson.org
713-745-2457
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert  

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