Molecular pathogenesis of Fanconi anemia: recent progress

Abstract

A rare genetic disease, Fanconi anemia (FA), now attracts broader attention from cancer biologists and basic researchers in the DNA repair and ubiquitin biology fields as well as from hematologists. FA is a chromosome instability syndrome characterized by childhood-onset aplastic anemia, cancer or leukemia susceptibility, and cellular hypersensitivity to DNA crosslinking agents. Identification of 11 genes for FA has led to progress in the molecular understanding of this disease. IntroductionMany hematologists are familiar with Fanconi anemia (FA) as a cause of childhood-onset aplastic anemia. However, this rare genetic disease now attracts broader attention from cancer biologists and basic researchers. FA is a rare chromosome instability syndrome characterized by aplastic anemia, cancer and leukemia susceptibility, and cellular hypersensitivity to interstrand DNA crosslinking agents, such as cisplatin, mitomycin C (MMC), diepoxybutane (DEB), and melphalan. [1][2][3] Treatment with these agents causes increased chromosome breakage in cells derived from patients with FA. 4 Because of this hypersensitivity to DNA crosslinking agents, many researchers have speculated that the primary defect of FA cells is in DNA damage response or DNA repair, although until recently direct evidence of a connection between FA and DNA repair had not been shown.Recent identification of the responsible genes for FA has changed our view of the molecular pathogenesis of the disease. FA can be divided into at least 12 complementation groups (A, B, C, D1, D2, E, F, G, I, J, L, and M) defined by cell fusion studies, and 11 of the 12 responsible FA genes have been identified (Table 1; Figure 1). [5][6][7][8] Proteins encoded by FA genes (FA proteins) include a ubiquitin ligase (FANCL/PHF9/ POG), 9 a monoubiquitinated protein (FANCD2), 10,11 a helicase (FANCJ/ BACH1/BRIP1), 7,8,12 a protein with helicase motifs and a nuclease motif (FANCM), and a well-known breast/ovarian cancer susceptibility protein (FANCD1/BRCA2). 13 FA proteins (including BRCA2) and another well-known breast/ovarian cancer susceptibility protein, BRCA1, cooperate in a common DNA repair process that is required for cellular resistance to DNA interstrand crosslinks (ICLs), and a concept of the Fanconi anemia-BRCA pathway 14 (or FA-BRCA network 15 ) has been proposed. Furthermore, molecular and functional interaction of FA proteins with proteins [ATM (ataxia-telangiectasia mutated), 16 MRE11, 17 BLM, [18][19][20]17,21 and ATR (ATM and Rad3-related) 22,23 ] responsible for other rare genetic chromosome instability syndromes [ataxia telangiectasia, 24 AT-like disorder, 25 Bloom syndrome, 26 Nijmegen breakage syndrome (NBS), 27 and Seckel syndrome, respectively] in DNA damage response is now evident. Therefore, the FA pathway appears to regulate DNA repair.Ubiquitination is a posttranslational modification in which a 76-residue small protein, ubiquitin, is covalently attached to a target protein (reviewed in Mani and Gelmann 28 ). Polyubiquitination is well known for its funct...

Fancd2 −/− mice have hematopoietic defects that can be partially corrected by resveratrol

“…[17][18][19][20] Similar to human FA patients, Fancd2 Ϫ/Ϫ mice have a higher incidence of tumors, a phenotype that occurs rarely in Fancc Ϫ/Ϫ or other models with a deficient FA core-complex gene. 16,21 However, the hematopoietic properties of Fancd2 Ϫ/Ϫ mice have not been fully characterized previously. FANCD2 is thought to play a central role in the FA/BRCA pathway and is well conserved among different multicellular eukaryotic species, whereas the majority of FA core complex genes do not exist in many lower eukaryotes.…”

FANCD2 Western blot as a diagnostic tool for Brazilian patients with Fanconi anemia

“…Studies by Smogorzewska et al (14) and Sims et al (29) suggest that previous monoubiquitination of FANCI is important for subsequent FANCD2 monoubiquitination. The activated isoform of FANCD2 (FANCD2L) is targeted to the nuclear foci where it functions in concert with BRCA1/BRCA2/RAD51 at the sites of DNA damage and repair (23,25,37).…”

“…A point mutation at amino acid residue 561, which is the site of monoubiquitination, abolishes its ability to correct sensitivity to these chromosome breakage agents. Mutations in any of the upstream FA genes also result in disruption of the FA/BRCA pathway leading to inefficient repair of the lesions and causing many of the clinical and cellular features of FA (23,26).…”

“…The activation of this complex induced by DNA replication or by DNA-damage results in monoubiquitination of FANCD2, which moves into areas of damaged chromatin to interact with downstream FA members (FANCD1/BRCA2, FANCJ, FANCN) and other DNA-repair proteins such as BRCA1 and RAD51. FANCD2 is the central protein that connects the FA/BRCA pathway to the homologous recombination-mediated DNA repair (18,19,23,(25)(26)(27)(28). The recently identified FANCI protein associates with FANCD2 and is the second monoubiquitinated component of the FA pathway (14,29).…”

“…A general model has been proposed for the FA pathway based on the response to DNA after exposure of cells to genotoxic stress or following replication arrests (22,23). In brief, eight of the cloned FA genes encode for proteins (FANCA, B, C, E, F, G, L, M), which are part of a large nuclear core complex with multiple subunits and E3 ubiquitin ligase activity (5,24).…”