title: Fanconi anemia D2 protein is an apoptotic target mediated by caspases.
abstract: FANCD2, a key factor in the FANC-BRCA1 pathway is monoubiquitinated and targeted to discrete nuclear foci following DNA damage. Since monoubiquitination of FANCD2 is a crucial indicator for cellular response to DNA damage, we monitored the fate of FANCD2 and its monoubiquitination following DNA damage. Disappearance of FANCD2 protein was induced following DNA damage in a dose-dependent manner, which correlated with degradation of BRCA1 and poly-ADP ribose polymerase (PARP), known targets for caspase-mediated apoptosis. Disappearance of FANCD2 was not affected by a proteasome inhibitor but was blocked by a caspase inhibitor. DNA damage-induced disappearance of FANCD2 was also observed in cells lacking FANCA, suggesting that disappearance of FANCD2 does not depend on FANC-BRCA1 pathway and FANCD2 monoubiquitination. In keeping with this, cells treated with TNF-α, an apoptotic stimulus without causing any DNA damage, also induced disappearance of FANCD2 without monoubiquitination. Together, our data suggest that FANCD2 is a target for caspase-mediated apoptotic pathway, which may be an early indicator for apoptotic cell death.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Su-Jung
authors.initials: SJ
authors.lastname: Park
authors.forename: Brian D
authors.initials: BD
authors.lastname: Beck
authors.forename: M Reza
authors.initials: MR
authors.lastname: Saadatzadeh
authors.forename: Laura S
authors.initials: LS
authors.lastname: Haneline
authors.forename: D Wade
authors.initials: DW
authors.lastname: Clapp
authors.forename: Suk-Hee
authors.initials: SH
authors.lastname: Lee
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D002945:Cisplatin / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004249:DNA Damage; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology; D057149:Ubiquitinated Proteins / Q000494:pharmacology / Q000502:physiology
chemical_list: D003432:Cross-Linking Reagents; D052236:Fanconi Anemia Complementation Group D2 Protein; D014409:Tumor Necrosis Factor-alpha; D057149:Ubiquitinated Proteins; D016685:Mitomycin; D020169:Caspases; D046988:Proteasome Endopeptidase Complex; D002945:Cisplatin