title: On the role of FAN1 in Fanconi anemia.
abstract: Fanconi anemia (FA) is a rare bone marrow failure disorder with defective DNA interstrand crosslink repair. Still, there are FA patients without mutations in any of the 15 genes individually underlying the disease. A candidate protein for those patients, FA nuclease 1 (FAN1), whose gene is located at chromosome 15q13.3, is recruited to stalled replication forks by binding to monoubiquitinated FANCD2 and is required for interstrand crosslink repair, suggesting that mutation of FAN1 may cause FA. Here we studied clinical, cellular, and genetic features in 4 patients carrying a homozygous 15q13.3 micro-deletion, including FAN1 and 6 additional genes. Biallelic deletion of the entire FAN1 gene was confirmed by failure of 3'- and 5'-PCR amplification. Western blot analysis failed to show FAN1 protein in the patients' cell lines. Chromosome fragility was normal in all 4 FAN1-deficient patients, although their cells showed mild sensitivity to mitomycin C in terms of cell survival and G(2) phase arrest, dissimilar in degree to FA cells. Clinically, there were no symptoms pointing the way to FA. Our results suggest that FAN1 has a minor role in interstrand crosslink repair compared with true FA genes and exclude FAN1 as a novel FA gene.
authors.affiliation: Genome Instability and DNA Repair Group, Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Trujillo
authors.forename: Leonardo B
authors.initials: LB
authors.lastname: Mina
authors.forename: Roser
authors.initials: R
authors.lastname: Pujol
authors.forename: Massimo
authors.initials: M
authors.lastname: Bogliolo
authors.forename: Joris
authors.initials: J
authors.lastname: Andrieux
authors.forename: Muriel
authors.initials: M
authors.lastname: Holder
authors.forename: Beatrice
authors.initials: B
authors.lastname: Schuster
authors.forename: Detlev
authors.initials: D
authors.lastname: Schindler
authors.forename: Jordi
authors.initials: J
authors.lastname: Surrallés
mesh_terms: D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002884:Chromosomes, Human, Pair 15; D004260:DNA Repair / Q000502:physiology*; D004261:DNA Replication / Q000502:physiology; D004706:Endodeoxyribonucleases; D005090:Exodeoxyribonucleases / Q000235:genetics* / Q000502:physiology*; D005199:Fanconi Anemia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D017353:Gene Deletion; D006720:Homozygote; D006801:Humans; D007223:Infant; D064251:Multifunctional Enzymes
chemical_list: D064251:Multifunctional Enzymes; D004706:Endodeoxyribonucleases; D005090:Exodeoxyribonucleases; C551063:FAN1 protein, human