Update of the human and mouse Fanconi anemia genes

Abstract

Fanconi anemia (FA) is a recessively inherited disease manifesting developmental abnormalities, bone marrow failure, and increased risk of malignancies. Whereas FA has been studied for nearly 90 years, only in the last 20 years have increasing numbers of genes been implicated in the pathogenesis associated with this genetic disease. To date, 19 genes have been identified that encode Fanconi anemia complementation group proteins, all of which are named or aliased, using the root symbol "FANC." Fanconi anemia subtype (FANC) proteins function in a common DNA repair pathway called "the FA pathway," which is essential for maintaining genomic integrity. The various FANC mutant proteins contribute to distinct steps associated with FA pathogenesis. Herein, we provide a review update of the 19 human FANC and their mouse orthologs, an evolutionary perspective on the FANC genes, and the functional significance of the FA DNA repair pathway in association with clinical disorders. This is an example of a set of genes--known to exist in vertebrates, invertebrates, plants, and yeast--that are grouped together on the basis of shared biochemical and physiological functions, rather than evolutionary phylogeny, and have been named on this basis by the HUGO Gene Nomenclature Committee (HGNC).

Fig. 1

Overview of FA pathway genes identified in eukaryotic lineages. Representative species include mammals (Homo sapiens, Mus musculus, and Gallus gallus), amphibian (African clawed toad, Xenopus laevis), fish (zebrafish, Danio rerio), sea squirt (Ciona intestinalis), insect (Drosophila melanogaster), worm (Caenorhabditis elegans), yeast (Saccharomyces cerevisiae), and plant (Arabidopsis thaliana). FANC genes are grouped into three classes. Group I includes nine genes that encode proteins that form the FA core complex; group II encodes FANCD2 and FANCI that form the D2/I complex; group III comprises eight genes that encode FA effector proteins that function downstream of D2/I complex. Lower eukaryotes tend to be missing orthologues of the FA core complex genes. A = FANCA, B = FANCB, C = FANCC, D2 = FANCD2, E = FANCE, F = FANCF, G = FANCG, I = FANCI, L = FANCL, M = FANCM, D1 = BRCA2/FANCD1, J = BRIP1/FANCJ, N = PALB2/FANCN, O = RAD51C/FANCO, P = SLX4/FANCP, Q = ERCC4/FANCQ/XPF, R = RAD51/FANCR, S = BRCA1/FANCS, T = UBE2T/FANCT. If we extend this gene family update to include prokaryotes, it might be noted that, whereas no orthologs of any of the 19 eukaryotic FANC genes exist in prokaryote genomes, RAD51 (as a nineteenth FANC member in living organisms) qualifies as a homologue of bacterial RecA

Fig. 2

FA/BRCA pathway and crosstalk between FA and other DNA repair pathways. In response to upstream DNA damage signaling (such as phosphorylation by ATR/ATM), in the FA/BRCA pathway [1], the FA core complex forms––comprising FANCA (A), FANCB (B), FANCC (C), FANCE (E), FANCF (F), FANCG (G), FANCM (M), and FANCL (L) proteins, plus FAAP20, FAAP24, and FAAP100 (FAAP). This core complex binds UBE2T(T) via FANCL, which then activates FANCD2/I dimers through mono-ubiquitination. The activated FANCD2/I (D2/I) complex then translocates to DNA - damage sites and recruits downstream FA effector proteins––including BRCA1 (S), BRCA2 (D1), RAD51 (R), BRIP1 (J), PALB2 (N), RAD51C (O), SLX4 (P), and ERCC4 (Q), plus other DNA repair molecules (such as FAN1) to the lesion site to repair damage. In the FANCM/BS pathway [2], the FA core complex binds to the BS complex by way of interactions between FANCM-RMI1 and TopoIIIα of the BS complex and translocates to the lesion site. In the FANCD2/ATM pathway [3], in response to ionizing radiation or ICL-inducing agents, FANCD2 is phosphorylated by ATM and co-localizes with the NMR complex to repair DNA damage or cause S-phase arrest. ICL interstrand cross-links, ATR ataxia-telangiectasia-Ser/Thr-protein kinase, ATM ataxia telangiectasia mutated kinase, FAAP FA-associated proteins, FAN1 FA-associated nuclease-1, BS Bloom’s syndrome protein, RMI1/2 RecQ-mediated genomic instability protein 1/2, TopoIIIα topoisomerase IIIα, NMR the NBS1/MRE11/RAD50 complex