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.