A mutation that frustrates DNA repair likely contributes to Fanconi anemia
After more than a century of technological refinements, zippers still get stuck. So do the molecular machines that routinely unzip the double helix of DNA in our cells after billions of years of evolution, and the results can be lethal.
In research to be published July 30 in Molecular Cell and already available online, scientists at Rockefeller University and colleagues show how a previously uncharacterized protein associated with the cancer-causing disorder Fanconi anemia might aid in repairing the broken zippers in our genes. When two strands of DNA remain stuck together, they supposed to make. This sticking point is one of the most deadly genetic perils, called an inter-strand crosslink, which threatens an average cell about 10 times a day.
“Repairing the inter-strand crosslink is a very complicated process,” says Agata Smogorzewska, head of the Laboratory of Genome Maintenance at Rockefeller, who led the research. “It takes lots of players, and if they don’t work correctly, the consequences can be terrible.” Thirteen proteins are known to be involved in the Fanconi anemia pathway, which repairs inter-strand crosslinks. If any one of them is damaged, the result is Fanconi anemia, a disorder that leads to bone marrow failure and leukemia, among other cancers, as well as many developmental abnormalities.
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Molecular Cell, Volume 39, Issue 1, 36-47, 9 July 2010 | Copyright © 2010 Elsevier Inc. All rights reserved. | 10.1016/j.molcel.2010.06.023
A Genetic Screen Identifies FAN1, a Fanconi Anemia-Associated Nuclease Necessary for DNA Interstrand Crosslink Repair
Agata Smogorzewska
,Rohini Desetty,Takamune T. Saito,Michael Schlabach,Francis P. Lach,Mathew E. Sowa,Alan B. Clark,Thomas A. Kunkel,J. Wade Harper,Monica P. Colaiácovo,Stephen J. Elledge
,Rohini Desetty,Takamune T. Saito,Michael Schlabach,Francis P. Lach,Mathew E. Sowa,Alan B. Clark,Thomas A. Kunkel,J. Wade Harper,Monica P. Colaiácovo,Stephen J. ElledgeHighlights
- FAN1 (KIAA1018) and EXDL2 were identified in a genetic screen in mammalian cells
- Loss of FAN1 or EXDL2 results in DNA crosslink sensitivity
- FAN1 localization to sites of DNA damage depends on the Fanconi anemia pathway and a UBZ domain of FAN1
- FAN1 possesses an intrinsic endonuclease and exonuclease activity that might be important for crosslink repair and replication restart
- Summary
- The Fanconi anemia (FA) pathway is responsible for interstrand crosslink repair. At the heart of this pathway is the FANCI-FAND2 (ID) complex, which, upon ubiquitination by the FA core complex, travels to sites of damage to coordinate repair that includes nucleolytic modification of the DNA surrounding the lesion and translesion synthesis. How the ID complex regulates these events is unknown. Here we describe a shRNA screen that led to the identification of two nucleases necessary for crosslink repair, FAN1 (KIAA1018) and EXDL2. FAN1 colocalizes at sites of DNA damage with the ID complex in a manner dependent on FAN1's ubiquitin-binding domain (UBZ), the ID complex, and monoubiquitination of FANCD2. FAN1 possesses intrinsic 5′-3′ exonuclease activity and endonuclease activity that cleaves nicked and branched structures. We propose that FAN1 is a repair nuclease that is recruited to sites of crosslink damage in part through binding the ubiquitinated ID complex through its UBZ domain.
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