RESUMO
Fanconi Anemia (FA) clinical phenotypes are heterogenous and rely on a mutation in one of the 22 FANC genes (FANCA-W) involved in a common interstrand DNA crosslink-repair pathway. A critical step in the activation of FA pathway is the monoubiquitination of FANCD2 and its binding partner FANCI. To better address the clinical phenotype associated with FANCI and the epistatic relationship with FANCD2, we created the first conditional inactivation model for FANCI in mouse. Fanci -/- mice displayed typical FA features such as delayed development in utero, microphtalmia, cellular sensitivity to mitomycin C, occasional limb abnormalities and hematological deficiencies. Interestingly, the deletion of Fanci leads to a strong meiotic phenotype and severe hypogonadism. FANCI was localized in spermatocytes and spermatids and in the nucleus of oocytes. Both FANCI and FANCD2 proteins co-localized with RPA along meiotic chromosomes, albeit at different levels. Consistent with a role in meiotic recombination, FANCI interacted with RAD51 and stimulated D-loop formation, unlike FANCD2. The double knockout Fanci-/- Fancd2-/- also showed epistatic relationship for hematological defects while being not epistatic with respect to generating viable mice in crosses of double heterozygotes. Collectively, this study highlights common and distinct functions of FANCI and FANCD2 during mouse development, meiotic recombination and hematopoiesis.
Assuntos
Reparo do DNA , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Anemia de Fanconi/genética , Animais , Células Cultivadas , Modelos Animais de Doenças , Anemia de Fanconi/metabolismo , Anemia de Fanconi/patologia , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oócitos/metabolismo , Rad51 Recombinase/genética , Rad51 Recombinase/metabolismo , Espermatócitos/metabolismoRESUMO
Fanconi Anemia is a rare autosomal recessive genetic disease with heterogenous phenotypes including myelosuppression, congenital malformations and heightened cancer predisposition. FA cells are highly sensitive to cross-linking agents. Since the 90's, at least 19 FANC proteins (FANCA to FANCT) have been identified as working together in a unique pathway detecting and triggering the repair of DNA crosslinks. Since then, the creation of animal models in various species (nematode, fruit fly, zebrafish and mouse) contributed to a better understanding of the physiopathology of the disease. This review aims to summarize the main discoveries made in these in vivo models, as well as to discuss some controversies that arose from these studies.