范可尼贫血和共济失调毛细血管扩张信号通路的汇聚。

Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways.

作者信息

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

机构信息

Department of Pediatric Oncology, Dana-Farber Cancer Institute and Department of Pediatrics, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

出版信息

Cell. 2002 May 17;109(4):459-72. doi: 10.1016/s0092-8674(02)00747-x.

DOI:10.1016/s0092-8674(02)00747-x

PMID:12086603

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.

摘要

范可尼贫血（FA）和共济失调毛细血管扩张症（AT）是临床上不同的常染色体隐性疾病，其特征为自发性染色体断裂和血液系统癌症。FA细胞对丝裂霉素C（MMC）高度敏感，而AT细胞对电离辐射（IR）高度敏感。在此，我们确定范可尼贫血蛋白FANCD2是FA与ATM损伤反应途径之间的一个联系。ATM在体外使FANCD2的丝氨酸222磷酸化。在IR照射后，该位点在体内也以ATM依赖的方式被磷酸化。FANCD2的磷酸化是激活S期检查点所必需的。FANCD2在S222位点上由ATM依赖的磷酸化以及FANCD2在K561位点上由FA途径依赖的单泛素化是调节离散细胞信号通路的独立翻译后修饰。FANCD2的双等位基因破坏导致对MMC和IR均高度敏感。