Regulation of the Fanconi anemia pathway Fanconi Anemia pathway Authored: Matthews, L, 2009-05-02 17:26:55 Edited: Matthews, L, 2009-05-20 15:51:04 Fanconi anemia (FA) is a genetic disease of genome instability characterized by congenital skeletal defects, aplastic anemia, susceptibility to leukemias, and cellular sensitivity to DNA damaging agents. Patients with FA have been categorized into at least 13 complementation groups (FA-A, -B, -C, -D1, -D2, -E, -F, -G, -I, -J, -L, -M, and -N). These complementation groups correspond to the genes FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCJ/BRIP1, FANCL, FANCM, and FANCN/PALB2. Although the functions of most of these proteins are mostly unknown, eight of them, FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM products together with AAP24 and FAAP100 form a nuclear complex termed the FA core complex. The core complex is essential for FANCD2 and FANCI monoubiquitination after DNA damage. FANCD2 and FANCI are mutually dependent on one another for their respective monoubiquitination. After DNA damage and during S phase, FANCD2 localizes to chromatin, forming foci that overlap those containing proteins involved in homologous recombination, such as BRCA1 and RAD51. The FA pathway is regulated by the deubiquitination of FANCD2 and the phosphorylation FANCD2 and FANCI. The USP1/UAF1 complex is responsible for deubiquitination of FANCD2 and negatively regulates the FA pathway (Cohn et al., 2007) ATR and ATM dependent phosphorylation of FANCD2 promotes the monoubiquitination of FANCD2 stimulating the FA pathway (Cohn and D'Andrea, 2008; Wang, 2007). Pubmed17768402 Pubmed18082604 Pubmed18995829 Reactome Database ID Release 43419524 Reactome, http://www.reactome.org ReactomeREACT_18410 Reviewed: Huang, TT, 2009-05-20 17:48:24 PathwayStep3013 PathwayStep3012 PathwayStep3011 PathwayStep3010 PathwayStep3017 Formation of the BRCA1-PALB2-BRCA2 complex Monoubiquitination of FANCD2 by the FA ubiquitin ligase complex Translocation of ub-FANCD2 and ub-FANCI to chromatin Monoubiquitination of FANCI by the FA ubiquitin ligase complex