title: Reduced FANCD2 influences spontaneous SCE and RAD51 foci formation in uveal melanoma and Fanconi anaemia.
abstract: Uveal melanoma (UM) is unique among cancers in displaying reduced endogenous levels of sister chromatid exchange (SCE). Here we demonstrate that FANCD2 expression is reduced in UM and that ectopic expression of FANCD2 increased SCE. Similarly, FANCD2-deficient fibroblasts (PD20) derived from Fanconi anaemia patients displayed reduced spontaneous SCE formation relative to their FANCD2-complemented counterparts, suggesting that this observation is not specific to UM. In addition, spontaneous RAD51 foci were reduced in UM and PD20 cells compared with FANCD2-proficient cells. This is consistent with a model where spontaneous SCEs are the end product of endogenous recombination events and implicates FANCD2 in the promotion of recombination-mediated repair of endogenous DNA damage and in SCE formation during normal DNA replication. In both UM and PD20 cells, low SCE was reversed by inhibiting DNA-PKcs (DNA-dependent protein kinase, catalytic subunit). Finally, we demonstrate that both PD20 and UM are sensitive to acetaldehyde, supporting a role for FANCD2 in repair of lesions induced by such endogenous metabolites. Together, these data suggest FANCD2 may promote spontaneous SCE by influencing which double-strand break repair pathway predominates during normal S-phase progression.
authors: The Institute for Cancer Studies, Department of Oncology, Faculty of Medicine Dentistry and Health Sciences, University of Sheffield, Sheffield, UK.
authors: P
authors: P
authors: Gravells
authors: L
authors: L
authors: Hoh
authors: S
authors: S
authors: Solovieva
authors: A
authors: A
authors: Patil
authors: E
authors: E
authors: Dudziec
authors: I G
authors: IG
authors: Rennie
authors: K
authors: K
authors: Sisley
authors: H E
authors: HE
authors: Bryant
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D004249:DNA Damage; D019175:DNA Methylation; D017931:DNA Primers; D004261:DNA Replication; D005199:Fanconi Anemia / Q000235:genetics*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics*; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D051135:Rad51 Recombinase / Q000235:genetics*; D012854:Sister Chromatid Exchange; D014604:Uveal Neoplasms / Q000235:genetics*
chemical_list: D017931:DNA Primers; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; C495153:RAD51 protein, human; D051135:Rad51 Recombinase