Recombinational repair of DNA double-strand damage - some key steps.ATM (ATM) is a protein kinase that is recruited and activated by DNA double-strand breaks. DNA double-strand damages also activate the Fanconi anemia core complex (FANCA/B/C/E/F/G/L/M). The FA core complex monoubiquitinates the downstream targets FANCD2 and FANCI. ATM activates (phosphorylates) CHEK2 and FANCD2 CHEK2 phosphorylates BRCA1. Ubiquinated FANCD2 complexes with BRCA1 and RAD51. The PALB2 protein acts as a hub, bringing together BRCA1, BRCA2 and RAD51 at the site of a DNA double-strand break, and also binds to RAD51C, a member of the RAD51 paralog complex RAD51B-RAD51C-RAD51D-XRCC2 (BCDX2). The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites.RAD51 plays a major role in homologous recombinational repair of DNA during double strand break repair. In this process, an ATP dependent DNA strand exchange takes place in which a single strand invades base-paired strands of homologous DNA molecules. RAD51 is involved in the search for homology and strand pairing stages of the process.
The clinical phenotype of mutational defects in all Fanconi anemia (FA) complementation groups is similar. This phenotype is characterized by progressive bone marrow failure, cancer proneness and typical birth defects. The main cellular phenotype is hypersensitivity to DNA damage, particularly inter-strand DNA crosslinks. The FA proteins interact through a multiprotein pathway. DNA interstrand crosslinks are highly deleterious damages that are repaired by homologous recombination involving coordination of FA proteins and breast cancer susceptibility gene 1 (BRCA1).
The Fanconi Anemia (FA) DNA repair pathway is essential for the recognition and repair of DNA interstrand crosslinks (ICL). A critical step in the pathway is the monoubiquitination of FANCD2 by the RING E3 ligase FANCL. FANCL comprises 3 domains, a RING domain that interacts with E2 conjugating enzymes, a central domain required for substrate interaction, and an N-terminal E2-like fold (ELF) domain. The ELF domain of FANCL is required to mediate a non-covalent interaction between FANCL and ubiquitin. The ELF domain is required to promote efficient DNA damage-induced FANCD2 monoubiquitination in vertebrate cells, suggesting an important function of ubiquitin binding by FANCL in vivo.
^Castillo P, Bogliolo M, Surralles J (2011). "Coordinated action of the Fanconi anemia and ataxia telangiectasia pathways in response to oxidative damage". DNA Repair (Amst.). 10 (5): 518–25. doi:10.1016/j.dnarep.2011.02.007. PMID21466974.
^Taniguchi T, Garcia-Higuera I, Andreassen PR, Gregory RC, Grompe M, D'Andrea AD (2002). "S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51". Blood. 100 (7): 2414–20. doi:10.1182/blood-2002-01-0278. PMID12239151.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
Agoulnik AI, Lu B, Zhu Q, et al. (2003). "A novel gene, Pog, is necessary for primordial germ cell proliferation in the mouse and underlies the germ cell deficient mutation, gcd". Hum. Mol. Genet. 11 (24): 3047–53. doi:10.1093/hmg/11.24.3047. PMID12417526.
Lu B, Bishop CE (2003). "Mouse GGN1 and GGN3, two germ cell-specific proteins from the single gene Ggn, interact with mouse POG and play a role in spermatogenesis". J. Biol. Chem. 278 (18): 16289–96. doi:10.1074/jbc.M211023200. PMID12574169.
Lu B, Bishop CE (2004). "Late onset of spermatogenesis and gain of fertility in POG-deficient mice indicate that POG is not necessary for the proliferation of spermatogonia". Biol. Reprod. 69 (1): 161–8. doi:10.1095/biolreprod.102.014654. PMID12606378.
Gurtan AM, Stuckert P, D'Andrea AD (2006). "The WD40 repeats of FANCL are required for Fanconi anemia core complex assembly". J. Biol. Chem. 281 (16): 10896–905. doi:10.1074/jbc.M511411200. PMID16474167.
Zhang J, Wang X, Lin CJ, et al. (2007). "Altered expression of FANCL confers mitomycin C sensitivity in Calu-6 lung cancer cells". Cancer Biol. Ther. 5 (12): 1632–6. doi:10.4161/cbt.5.12.3351. PMID17106252.