New Players Complement the Team

RESEARCH HIGHLIGHTS

DOI: 10.1038/nrm2193

URLs FANCI http://www.ncbi.nlm.nih.gov/ entrez/query.fcgi?db=gene&c md=Retrieve&dopt=full_ report&list_uids=55215

FANCD2 http://ca.expasy.org/uniprot/ Q9BXW9

DNA REPAIR New players complement the team

Fanconi anaemia (FA) is a chromosome showed that FANCI is monoubiquitylated in a found a candidate gene (KIAA1794) that was instability and development disorder that falls DNA-damage-inducible manner by the FA core mutated in eight patients and which they into 13 complementation groups, 12 of which complex, and that FANCI monoubiquitylation subsequently identified as FANCI. have been linked to distinct genes. However, is important for its recruitment to damage- Finally, Ling et al. identified a new the FA-I complementation group has induced nuclear foci. Surprisingly, the component of the FA core complex, the remained uncharacterized. Several new monoubiquitylation of FANCI also depended 100-kDa polypeptide FAAP100, by mass studies report the identification of new on the presence of FANCD2. This relationship spectrometry. FAAP100 forms a stable factors — including the protein associated subcomplex with FANCL and FANCB that can with the FA-I group — that are crucial for the be biochemically purified. Assembly of the FA-associated DNA-damage response. subcomplex stabilizes the components and Using a proteomics screen for DNA- The reciprocal ubiquitylation protects them against degradation. Nuclear damage-induced phosphorylation substrates dependency between FANCD2 localization of the subcomplex is regulated by of ATM and ATR kinases (which regulate the and FANCI is also puzzling. other components of the FA core complex. FA-mediated DNA-repair pathway) coupled But their physiological FAAP100 is essential for the stability of the FA with a genetic screen for DNA-damage core complex and for monoubiquitylation of its sensitivity, Smogorzewska et al. identified an significance is real… crucial substrate, FANCD2. In addition, uncharacterized protein, KIAA1794, which FAAP100-knockout cells display the hallmarks confers resistance to a DNA-crosslinking agent of FA but, so far, no FAAP100 mutations have (mitomycin C; MMC). They showed that the is reciprocal, because depletion of FANCI been identified in patients with FA. The corresponding gene matched the FA-I resulted in diminished ubiquitylation of authors propose that the FA core complex complementation group and was hence FANCD2 and a reduction in FANCD2 levels. consists of multiple subcomplexes, the renamed FANCI. Knockdown of FANCI in the There is evidence that FANCI and FANCD2 biochemical purification of which could presence of MMC resulted in cytogenetic form a complex, but it is not clear whether the eventually allow reconstitution of the full abnormalities and hypersensitivity, defective effect of FANCI knockdown on FANCD2 complex. G2–M and intra-S-phase checkpoints, and protein stability is due to the loss of this Arianne Heinrichs reduced homologous recombination following interaction. The reciprocal ubiquitylation DNA double-strand breaks — which are all dependency between FANCD2 and FANCI is ORIGINAL RESEARCH PAPERS Smogorzewska, A. et al. typical cellular features in patients with FA. also puzzling. But their physiological Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell 129, 289–301 Moreover, FANCI localized to DNA-damage- significance is real: Smogorzewska et al. were (2007) | Sims, A. E. et al. FANCI is a second monoubiquitinated induced nuclear foci and colocalized with able to complement three FA phenotypes member of the Fanconi anemia pathway. Nature Struct. Mol. Biol. 25 April 2007 (doi:10.1038/nsmb1252) | Dorsman, J. C. FANCD2. (MMC hypersensitivity, failure to et al. Identification of the Fanconi anemia complementation FANCD2 is monoubiquitylated by the FA monoubiquitylate FANCD2, and chromosome group I gene, FANCI. Cell. Oncol. 29, 211–218 (2007) | Ling, C. core complex, which consists of eight FA breakage) in FANCI-defective cells with et al. FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway. EMBO J. proteins and has E3 ubiquitin ligase activity. retrovirally expressed FANCI. Supporting the 26, 2104–2114 (2007) Sims et al. carried out a FANCD2-based biochemical characterization of FANCI, FURTHER READING Huang, T. T. & D’Andrea, A. D. sequence homology search and identified Dorsman et al. studied FA-I families using a Regulation of DNA repair by ubiquitylation. Nature Rev. Mol. Cell Biol. 7, 323–334 (2006) FANCI as a potential substrate. Both studies classic genetic linkage analysis approach and