Nature Structural & Molecular Biology
12, 763 - 771 (2005)
Published online: 21 August 2005; | doi:10.1038/nsmb981
The vertebrate Hef ortholog is a component of the Fanconi anemia tumor-suppressor pathwayGeorgina Mosedale1, 3, Wojciech Niedzwiedz1, 3, Arno Alpi1, 3, Franco Perrina1, Jose B Pereira-Leal1, Mark Johnson1, Frederic Langevin1, Paul Pace1
& Ketan J Patel1, 21
Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK. 2
Department of Medicine, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QH, UK. 3
These authors contributed equally to this work.
Correspondence should be addressed to Ketan J Patel kjp@mrc-lmb.cam.ac.uk The helicase-associated endonuclease for fork-structured DNA (Hef) is an archaeabacterial protein that processes blocked replication forks. Here we have isolated the vertebrate Hef ortholog and investigated its molecular function. Disruption of this gene in chicken DT40 cells results in genomic instability and sensitivity to DNA cross-links. The similarity of this phenotype to that of cells lacking the Fanconi anemia−related (FA) tumor-suppressor genes led us to investigate whether Hef functions in this pathway. Indeed, we found a genetic interaction between the FANCC and Hef genes. In addition, Hef is a component of the FA nuclear protein complex that facilitates its DNA damage−inducible chromatin localization and the monoubiquitination of the FA protein FANCD2. Notably, Hef interacts directly with DNA structures that are intermediates in DNA replication. This discovery sheds light on the origins, regulation and molecular function of the FA tumor-suppressor pathway in the maintenance of genome stability.
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