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XB-ART-890
Mol Cell Biol January 1, 2006; 26 (2): 425-37.

Fanconi anemia proteins are required to prevent accumulation of replication-associated DNA double-strand breaks.

Sobeck A , Stone S , Costanzo V , de Graaf B , Reuter T , de Winter J , Wallisch M , Akkari Y , Olson S , Wang W , Joenje H , Christian JL , Lupardus PJ , Cimprich KA , Gautier J , Hoatlin ME .


Abstract
Fanconi anemia (FA) is a multigene cancer susceptibility disorder characterized by cellular hypersensitivity to DNA interstrand cross-linking agents such as mitomycin C (MMC). FA proteins are suspected to function at the interface between cell cycle checkpoints, DNA repair, and DNA replication. Using replicating extracts from Xenopus eggs, we developed cell-free assays for FA proteins (xFA). Recruitment of the xFA core complex and xFANCD2 to chromatin is strictly dependent on replication initiation, even in the presence of MMC indicating specific recruitment to DNA lesions encountered by the replication machinery. The increase in xFA chromatin binding following treatment with MMC is part of a caffeine-sensitive S-phase checkpoint that is controlled by xATR. Recruitment of xFANCD2, but not xFANCA, is dependent on the xATR-xATR-interacting protein (xATRIP) complex. Immunodepletion of either xFANCA or xFANCD2 from egg extracts results in accumulation of chromosomal DNA breaks during replicative synthesis. Our results suggest coordinated chromatin recruitment of xFA proteins in response to replication-associated DNA lesions and indicate that xFA proteins function to prevent the accumulation of DNA breaks that arise during unperturbed replication.

PubMed ID: 16382135
PMC ID: PMC1346898
Article link: Mol Cell Biol
Grant support: [+]
Genes referenced: atr atrip fanca fancd2
GO keywords: DNA replication checkpoint [+]

Disease Ontology terms: pancytopenia [+]
OMIMs: FANCONI ANEMIA, COMPLEMENTATION GROUP D2; FANCD2 [+]
References [+] :
Andreassen, ATR couples FANCD2 monoubiquitination to the DNA-damage response. 2004, Pubmed


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