Convergence of the Fanconi Anemia and Ataxia Telangiectasia Signaling Pathways

• Published in: Cell 2002-05, Vol.109 (4), p.459-472
• Main Authors: Taniguchi, Toshiyasu, Garcia-Higuera, Irene, Xu, Bo, Andreassen, Paul R., Gregory, Richard C., Kim, Seong-Tae, Lane, William S., Kastan, Michael B., D'Andrea, Alan D.
• Format: Article
• Language: English
• Subjects: Ataxia Telangiectasia - genetics; Ataxia Telangiectasia - metabolism; Ataxia Telangiectasia - physiopathology; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; Cell Line, Transformed; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cell Nucleus - radiation effects; DNA-Binding Proteins; Fanconi Anemia - genetics; Fanconi Anemia - metabolism; Fanconi Anemia - physiopathology; Fanconi Anemia Complementation Group D2 Protein; G1 Phase - drug effects; G1 Phase - radiation effects; G2 Phase - drug effects; G2 Phase - radiation effects; Genes, cdc - drug effects; Genes, cdc - radiation effects; HeLa Cells; Humans; Mitomycin - pharmacology; Mutation - drug effects; Mutation - radiation effects; Nuclear Proteins - deficiency; Nuclear Proteins - genetics; Nucleic Acid Synthesis Inhibitors - pharmacology; Phosphorylation - radiation effects; Phosphoserine - antagonists & inhibitors; Phosphoserine - metabolism; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Radiation, Ionizing; S Phase - drug effects; S Phase - genetics; S Phase - radiation effects; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - radiation effects; Tumor Suppressor Proteins; Ubiquitin - genetics; Ubiquitin - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(02)00747-X

Fanconi anemia (FA) and ataxia telangiectasia (AT) are clinically distinct autosomal recessive disorders characterized by spontaneous chromosome breakage and hematological cancers. FA cells are hypersensitive to mitomycin C (MMC), while AT cells are hypersensitive to ionizing radiation (IR). Here, we identify the Fanconi anemia protein, FANCD2, as a link between the FA and ATM damage response pathways. ATM phosphorylates FANCD2 on serine 222 in vitro. This site is also phosphorylated in vivo in an ATM-dependent manner following IR. Phosphorylation of FANCD2 is required for activation of an S phase checkpoint. The ATM-dependent phosphorylation of FANCD2 on S222 and the FA pathway-dependent monoubiquitination of FANCD2 on K561 are independent posttranslational modifications regulating discrete cellular signaling pathways. Biallelic disruption of FANCD2 results in both MMC and IR hypersensitivity.