Journal
CELL
Volume 109, Issue 4, Pages 459-472Publisher
CELL PRESS
DOI: 10.1016/S0092-8674(02)00747-X
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Funding
- NCI NIH HHS [CA71387, CA21765] Funding Source: Medline
- NHLBI NIH HHS [R01HL52725, P01HL54785] Funding Source: Medline
- NIDDK NIH HHS [R01DK43889] Funding Source: Medline
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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.
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