Alternative titles; symbols
HGNC Approved Gene Symbol: FAAP100
Cytogenetic location: 17q25.3 Genomic coordinates (GRCh38) : 17:81,539,891-81,553,133 (from NCBI)
FAAP100 is a component of the Fanconi anemia (FA; 227650) core complex and is required for core complex stability and FANCD2 (227646) monoubiquitination (Ling et al., 2007).
By use of an FANCA (607139) antibody, Meetei et al. (2003) purified a Fanconi anemia (FA) core complex containing 5 known Fanconi anemia (see 227650) proteins and 4 unknown components, including 1 with a molecular mass of 100 kD, designated FAAP100. By mass spectrometry, Ling et al. (2007) identified FAAP100 as LOC80233 (C17ORF70). They cloned a full-length C17ORF70 cDNA, which encodes a deduced 881-amino acid protein with a coiled-coil domain. The protein sequence is conserved in vertebrates.
Using immunoprecipitation experiments, Ling et al. (2007) confirmed that FAAP100 is a component of the FA core complex. Using a mammalian 2-hybrid assay, they showed that FAAP100 interacts with FANCB (300515) and FANCL (608111) and forms a stable complex with them. The nuclear localization of FAAP100 was defective in cells with deficiency of FANCA or FANCM (609644). When FAAP100 was depleted in HeLa cells with siRNA oligos, the other components of the core complex also were reduced. Ling et al. (2007) created a knockout chicken B-cell line for the avian FAAP100 gene and found that the cellular phenotype had the hallmarks of Fanconi anemia, including hypersensitivity to DNA crosslinking drugs and MMC-induced chromosomal breakage. Ling et al. (2007) concluded that FAAP100 is an essential component of the FA-BRCA (see 600185)-associated network that responds to DNA damage.
Cryoelectron Microscopy
Shakeel et al. (2019) reconstituted an active, recombinant Fanconi anemia core complex, and used cryoelectron microscopy and mass spectrometry to determine its structure. The FA core complex comprises 2 central dimers of the FANCB and FAAP100 subunits, flanked by 2 copies of the RING finger subunit FANCL. These 2 heterotrimers act as a scaffold to assemble the remaining 5 subunits, resulting in an extended asymmetric structure. Destabilization of the scaffold would disrupt the entire complex, resulting in a nonfunctional FA pathway. Thus, the structure provides a mechanistic basis for the low numbers of patients with mutations in FANCB, FANCL, and FAAP100. Despite a lack of sequence homology, FANCB and FAAP100 adopt similar structures. The 2 FANCL subunits are in different conformations at opposite ends of the complex, suggesting that each FANCL has a distinct role. Shakeel et al. (2019) suggested that this structural and functional asymmetry of dimeric RING finger domains may be a general feature of E3 ligases.
Ling, C., Ishiai, M., Ali, A. M., Medhurst, A. L., Neveling, K., Kalb, R., Yan, Z., Xue, Y., Oostra, A. B., Auerbach, A. D., Hoatlin, M. E., Schindler, D., Joenje, H., de Winter, J. P., Takata, M., Meetei, A. R., Wang, W. FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway. EMBO J. 26: 2104-2114, 2007. [PubMed: 17396147] [Full Text: https://doi.org/10.1038/sj.emboj.7601666]
Meetei, A. R., Sechi, S., Wallisch, M., Yang, D., Young, M. K., Joenje, H., Hoatlin, M. E., Wang, W. A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome. Molec. Cell. Biol. 23: 3417-3426, 2003. [PubMed: 12724401] [Full Text: https://doi.org/10.1128/MCB.23.10.3417-3426.2003]
Shakeel, S., Rajendra, E., Alcon, P., O'Reilly, F., Chorev, D. S., Maslen, S., Degliesposti, G., Russo, C. J., He, S., Hill, C. H., Skehel, J. M., Scheres, S. H. W., Patel, K. J., Rappsilber, J., Robinson, C. V., Passmore, L. A. Structure of the Fanconi anaemia monoubiquitin ligase complex. Nature 575: 234-237, 2019. [PubMed: 31666700] [Full Text: https://doi.org/10.1038/s41586-019-1703-4]