Papadopoulo Dora, Moustacchi Ethel
Institut Curie, Section de recherche, UMR 218 CNRS, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
Med Sci (Paris). 2005 Aug-Sep;21(8-9):730-6. doi: 10.1051/medsci/2005218-9730.
Fanconi anemia (FA), a rare inherited disorder, exhibits a complex phenotype including progressive bone marrow failure, congenital malformations and increased risk of cancers, mainly acute myeloid leukaemia. At the cellular level, FA is characterized by hypersensitivity to DNA cross-linking agents and by high frequencies of induced chromosomal aberrations, a property used for diagnosis. FA results from mutations in one of the eleven FANC (FANCA to FANCJ) genes. Nine of them have been identified. In addition, FANCD1 gene has been shown to be identical to BRCA2, one of the two breast cancer susceptibility genes. Seven of the FANC proteins form a complex, which exists in four different forms depending of its subcellular localisation. Four FANC proteins (D1(BRCA2), D2, I and J) are not associated to the complex. The presence of the nuclear form of the FA core complex is necessary for the mono-ubiquitinylation of FANCD2 protein, a modification required for its re-localization to nuclear foci, likely to be sites of DNA repair. A clue towards understanding the molecular function of the FANC genes comes from the recently identified connection of FANC to the BRCA1, ATM, NBS1 and ATR genes. Two of the FANC proteins (A and D2) directly interact with BRCA1, which in turn interacts with the MRE11/RAD50/NBS1 complex, which is one of the key components in the mechanisms involved in the cellular response to DNA double strand breaks (DSB). Moreover, ATM, a protein kinase that plays a central role in the network of DSB signalling, phosphorylates in vitro and in vivo FANCD2 in response to ionising radiations. Moreover, the NBS1 protein and the monoubiquitinated form of FANCD2 seem to act together in response to DNA crosslinking agents. Taken together with the previously reported impaired DSB and DNA interstrand crosslinks repair in FA cells, the connection of FANC genes to the ATM, ATR, NBS1 and BRCA1 links the FANC genes function to the finely orchestrated network involved in the sensing, signalling and repair of DNA replication-blocking lesions.
范可尼贫血（FA）是一种罕见的遗传性疾病，表现出复杂的表型，包括进行性骨髓衰竭、先天性畸形以及癌症风险增加，主要是急性髓系白血病。在细胞水平上，FA的特征是对DNA交联剂高度敏感以及诱导染色体畸变的频率较高，这一特性用于诊断。FA是由11个FANC（FANCA至FANCJ）基因中的一个发生突变引起的。其中9个已被鉴定出来。此外，FANCD1基因已被证明与BRCA2相同，BRCA2是两个乳腺癌易感基因之一。7种FANC蛋白形成一个复合物，根据其亚细胞定位存在四种不同形式。4种FANC蛋白（D1（BRCA2）、D2、I和J）不与该复合物相关。FA核心复合物的核形式的存在对于FANCD2蛋白的单泛素化是必需的，这种修饰是其重新定位到核灶所必需的，核灶可能是DNA修复的位点。理解FANC基因分子功能的一个线索来自最近发现的FANC与BRCA1、ATM、NBS1和ATR基因的联系。两种FANC蛋白（A和D2）直接与BRCA1相互作用，而BRCA又与MRE11/RAD50/NBS1复合物相互作用，该复合物是细胞对DNA双链断裂（DSB）反应机制中的关键成分之一。此外，ATM是一种在DSB信号网络中起核心作用的蛋白激酶，在体外和体内对电离辐射的反应中使FANCD2磷酸化。此外，NBS1蛋白和FANCD2的单泛素化形式似乎在对DNA交联剂的反应中共同起作用。结合先前报道的FA细胞中DSB和DNA链间交联修复受损，FANC基因与ATM、ATR、NBS1和BRCA1之间的联系将FANC基因的功能与参与DNA复制阻断损伤的感知、信号传导和修复的精细协调网络联系起来。
