The vertebrate Hef ortholog is a component of the Fanconi anemia tumor-suppressor pathway.
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.
Mosedale
Georgina
G
Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK.
Niedzwiedz
Wojciech
W
Alpi
Arno
A
Perrina
Franco
F
Pereira-Leal
Jose B
JB
Johnson
Mark
M
Langevin
Frederic
F
Pace
Paul
P
Patel
Ketan J
KJ
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D030161:Avian Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002645:Chickens / Q000235:genetics / Q000378:metabolism; D017124:Conserved Sequence; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004265:DNA Helicases / Q000378:metabolism; D004260:DNA Repair; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism*; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D042822:Genomic Instability; D006801:Humans; D009687:Nuclear Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D030161:Avian Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C497651:FANCC protein, human; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D004247:DNA; D004720:Endonucleases; D000251:Adenosine Triphosphatases; D004265:DNA Helicases