Fanconi anemia D2 protein is an apoptotic target mediated by caspases

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 dama...

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Published in:Journal of cellular biochemistry 2011-09, Vol.112 (9), p.2383-2391
Main Authors: Park, Su-Jung, Beck, Brian D., Saadatzadeh, M. Reza, Haneline, Laura S., Clapp, D. Wade, Lee, Suk-Hee
Format: Article
Language:English
Subjects:
Apoptosis
Caspase
Caspases - metabolism
Cisplatin
Cisplatin - pharmacology
Cross-Linking Reagents - pharmacology
DNA Damage
DNA repair
Fanconi anemia
Fanconi Anemia Complementation Group D2 Protein - metabolism
HeLa Cells
Humans
Mitomycin - pharmacology
Mitomycin C
Proteasome Endopeptidase Complex - metabolism
Tumor Necrosis Factor-alpha - pharmacology
Tumor Necrosis Factor-alpha - physiology
Ubiquitinated Proteins - pharmacology
Ubiquitinated Proteins - physiology
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Summary: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. J. Cell. Biochem. 112: 2383–2391, 2011. © 2011 Wiley‐Liss, Inc.
ISSN:0730-2312
1097-4644
DOI:10.1002/jcb.23161