Abstracts
Résumé
Des mutations dans les gènes FANC sont responsables de l’anémie de Fanconi (AF), une maladie génétique de phénotype complexe incluant une pancytopénie, des malformations congénitales et une prédisposition élevée au cancer. L’augmentation par les agents pontant l’ADN de la fréquence des aberrations chromosomiques, une caractéristique de l’AF, est utilisée pour le diagnostic. Parmi les onze gènes FANC, neuf sont identifiés. Huit de ces gènes sont localisés sur des autosomes, tandis que FANCB est situé sur le chromosome X. L'un des gènes FANC est BRCA2, impliqué dans la prédisposition génétique au cancer du sein et/ou de l’ovaire. Sept des protéines FANC s’associent pour former un complexe à géométrie variable dépendant de sa localisation subcellulaire, tandis que FANCD1 (BRCA2), FANCD2, FANCI et FANCJ ne sont pas associées au complexe. La mono-ubiquitinylation de FANCD2, dépendante du complexe, jouerait un rôle important dans la gestion des pontages de l’ADN. Les protéines FANC et BRCA1, étroitement associées, participent, entre autres, avec les protéines ATM, NBS1 et ATR, à un réseau multiprotéique impliqué dans la détection, la signalisation et la réparation des lésions bloquant la réplication de l’ADN.
Summary
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.
Appendices
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