Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways |
| |
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 |
| |
Institution: | Department of Pediatric Oncology, Dana-Farber Cancer Institute and Department of Pediatrics, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. |
| |
Abstract: | 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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|