Fanconi anemia: join the club!

Abstract

Fanconi anemia (FA) syndrome is a member of the family of chromosomal instability syndromes, which includes ataxia telangiectasia (AT), Bloom syndrome (BS) and Nijmegen breakage syndrome (NBS). These syndromes are characterized by spontaneous chromosomal breakage, and accumulating data demonstrate the anticipated role in DNA maintenance of the genes causing these syndromes. For FA, direct evidence for this was lacking. Although five FA genes have been cloned so far from the seven known FA complementation groups, the lack of apparent homology of FA proteins to anything in the database or even themselves leaves their biochemical function enigmatic. Molecular evidence that all FA proteins function in a common pathway comes from the observation that the FA-A, -C, -G and -F proteins form a complex that is disrupted in cells of other FA complementation groups, including -B and -E. Recent cloning 1xPositional cloning of a novel Fanconi anemia gene, FANCD2. Timmers, C. et al. Mol. Cell. 2001; 7: 241–248Abstract | Full Text | Full Text PDF | PubMed | Scopus (293)See all References1 and subsequent analysis 2xInteraction of the Fanconi anemia proteins and BRCA1 in a common pathway. Garcia-Higuera, I. et al. Mol. Cell. 2001; 7: 249–262Abstract | Full Text | Full Text PDF | PubMed | Scopus (831)See all References2 of the FA-D2 gene has mapped its function downstream of the other FA genes and has provided an important lead to the long-sought function of the FA proteins. Although the FAD2 protein sequence again revealed no functional clues, Garcia-Higuera et al.2xInteraction of the Fanconi anemia proteins and BRCA1 in a common pathway. Garcia-Higuera, I. et al. Mol. Cell. 2001; 7: 249–262Abstract | Full Text | Full Text PDF | PubMed | Scopus (831)See all References2 discovered that FAD2 can be found in a mono-ubiquitinated form under some circumstances – but only when the other FA proteins are functional. For instance, FAD2 ubiquitination is induced by DNA damage, which drives the protein from a diffuse nuclear distribution to profound nuclear spots. FAD2 spots colocalize with BRCA1 in so-called ‘ionizing-radiation-inducible foci’ that contain other proteins implicated in DNA repair such as Rad51 or the Rad50–Mre11–NBS complex. The observation is substantiated by specific co-immunoprecipitation of the ubiquitinated form of FAD2 by BRCA1, and the fact that formation of FAD2 foci and DNA-damage-induced ubiquitination of FAD2 are impaired in BRCA1−/− cells.Does this mean that FA proteins are finally taken up in the realm of DNA repair proteins? It might appear so, but it remains to be seen what exactly it is they do and how they intermingle with BRCA1-associated DNA repair and recombination events. The fact that FAD2 spots are also seen during S phase and that FAD2 localizes to synaptonemal complexes in meiotic cells suggests a more general function for FA proteins than mere DNA repair.