FA complex
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Seven Fanconi anemia-associated proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG and FANCL) form a nuclear Fanconi anemia core complex that activates the monoubiquitination of FANCD2, targeting FANCD2 to BRCA1-containing nuclear foci. Cells from individuals with Fanconi anemia of complementation groups D1 and J (FA-D1 and FA-J) have normal FANCD2 ubiquitination.
Components
Fanconi anemia complementation group genes (FANC)
12 complementations groups
| Locus | Gene | MIM | Location | |
| FANCA | FANCA | MIM.607139 | 16q24.3 | |
| FANCB | FAAP95 | MIM.300514 | Xp22.31 | |
| FANCC | FANCC | MIM.227645 | 9p22.3 | |
| FANCD1 | BRCA2 | MIM.605724 | 13q12.3 | |
| FANCD2 | FANCD2 | MIM.227646 | 3p25.3 | |
| FANCE | FANCE | MIM.600901 | 6p22-p21 | |
| FANCF | FANCF | MIM.603467 | 11p15 | |
| FANCG | XRCC9 | MIM.602956 | 9p13 | |
| FANCH | ||||
| FANCI | ||||
| FANCJ | BRIP1 | MIM.605882 | 17q22 | |
| FANCL | PHF9 | MIM.608111 | 2p16.1 |
5 known proteins (2003)
Pathogeny
An increasing number of genes are involved in FA, including the breast cancer susceptibility gene BRCA2. Five of the FA proteins (FANCA, FANCC, FANCE, FANCF and FANCG) assemble in a proteic complex called "FA complex" that is required for FANCD2 activation in response to DNA crosslinks.
Active FANCD2 then interacts with BRCA1 and forms discrete nuclear foci. FANCD2 is independently phosphorylated by ATM (the protein whose gene is mutated in ataxia telangiectasia) in response to ionizing radiation.
crosstalk with ATM, BRCA1 and BRCA2, involved in xenobiotic and reactive oxygen species metabolism, apoptosis, cell cycle control and telomere stability
Fanconi anemia proteins (FANCs) function in a DNA damage response pathway involving breast cancer susceptibility gene products, BRCA1 and BRCA2.
A key step in this pathway is monoubiquitination of FANCD2, resulting in the redistribution of FANCD2 to nuclear foci containing BRCA1. The underlying mechanism is unclear because the five Fanconi anemia proteins known to be required for this ubiquitination have no recognizable ubiquitin ligase motifs.
Fanconi anemia is an autosomal recessive disorder characterised by progressive bone marrow failure and an increased risk of cancer, most commonly acute myeloid leukaemia. Patients with this disease have chronologically accelerated telomere shortening. Cells from patients with Fanconi anemia have increased sensitivity to DNA crosslinking agents.
Fanconi anemia can arise from mutations in different genes, including the breast cancer susceptibility gene BRCA2. These and other findings firmly establish a direct role for Fanconi anaemia group proteins in the response to DNA damage.
In view of the raised oxidative stress sensitivity of Fanconi anemia cells, an increased rate of cell turnover could chronologically accelerate telomere shortening.
Alternatively, a faster rate of telomere shortening with each cell division could result from increased telomere damage. Cells of patients with ataxia telangiectasia show increased telomere damage, but immortal ataxia telangiectasia cell lines do not differ from controls in any measured variable of telomere length maintenance. Therefore, rates of telomere shortening will have to be measured directly in different cell types from individuals with Fanconi anemia and from healthy people, to establish a direct effect of disease on rate of telomere loss.
See also
Fanconi anemia protein complex (FA complex)
PHF9 (ubiquitin ligase activity)
References
Venkitaraman AR. Tracing the network connecting BRCA and Fanconi anaemia proteins. Nat Rev Cancer. 2004 Apr;4(4):266-76. PMID: 15057286
D?Andrea AD, Grompe M. The Fanconi anaemia/BRCA pathway. Nat Rev Cancer. 2003 Jan;3(1):23-34. PMID: 12509764
Bogliolo M, Cabre O, Callen E, Castillo V, Creus A, Marcos R, Surralles J. The Fanconi anaemia genome stability and tumour suppressor network. Mutagenesis. 2002 Nov;17(6):529-38. PMID: 12435850
Zdzienicka MZ, Arwert F. Breast cancer and Fanconi anemia: what are the connections? Trends Mol Med. 2002 Oct;8(10):458-60. PMID: 12383764
Wong JC, Buchwald M. Disease model: Fanconi anemia. Trends Mol Med. 2002 Mar;8(3):139-42. PMID: 11879775
Grompe M, D?Andrea A. Fanconi anemia and DNA repair. Hum Mol Genet. 2001 Oct 1;10(20):2253-9. PMID: 11673408