Recent discoveries in the molecular pathogenesis of the inherited bone marrow failure syndrome Fanconi anemia

Abstract

Fanconi anemia (FA) is a rare autosomal and X-linked genetic disease characterized by congenital abnormalities, progressive bone marrow failure (BMF), and increased cancer risk during early adulthood. The median lifespan for FA patients is approximately 33years. The proteins encoded by the FA genes function together in the FA-BRCA pathway to repair DNA damage and to maintain genome stability. Within the past two years, five new FA genes have been identified-RAD51/FANCR, BRCA1/FANCS, UBE2T/FANCT, XRCC2/FANCU, and REV7/FANCV-bringing the total number of disease-causing genes to 21. This review summarizes the discovery of these new FA genes and describes how these proteins integrate into the FA-BRCA pathway to maintain genome stability and critically prevent early-onset BMF and cancer.

Keywords: DNA repair; Fanconi anemia; Genome instability; Homologous recombination; Ubiquitin.

Figure 1

Schematic of FANCD2 and FANCI monoubiquitination. Following exposure to DNA damaging agents and during S-phase of the cell cycle, the FANCM anchor complex, comprising FANCM, FAAP24, FAAP16/MHF1 and FAAP10/MHF2, recognizes the damage, remodels the fork, and promotes the recruitment of the FA core complex. The FA core complex, which is comprised of three sub-complexes - FANCB/FANCL/FAAP100, FANCC/FANCE/FANCF, and FANCA/FANCG/FAAP100 - together with the E2 ubiquitin-conjugating enzyme UBE2T/FANCT, constitutes an active multisubunit E2/E3 ubiquitination enzyme complex. This E2/E3 enzyme complex catalyzes the site-specific monoubiquitination of FANCD2 K561 and FANCI K523.

Figure 2

Schematic of downstream steps of the FA pathway. During the later stages of ICL repair, SLX4/FANCP and ERCC4/FANCQ catalyze the unhooking of the ICL (Step 1). The unhooked ICL is then bypassed by Polζ (Step 2). REV7/FANCV is a structural component of Polζ that enhances the polymerase activity of the catalytic subunit, REV3. Downstream of FANCD2 and FANCI monoubiquitination, BRCA2/FANCD1, BRIP1/FANCJ, PALB2/FANCN, RAD51C/FANCO, RAD51/FANCR, BRCA1/FANCS, and XRCC2/FANCU all function cooperatively to repair the remaining broken duplex by homologous recombination (HR). Following 5′–3′ DNA strand resection, RAD51/FANCR forms nucleoprotein filaments on single-stranded DNA and catalyzes homologous pairing and DNA strand invasion. BRCA2/FANCD1, PALB2/FANCN, RAD51C/FANCO, and XRCC2/FANCU facilitate these RAD51/FANCR-mediated processes.