FANCI is a second monoubiquitinated member of the Fanconi anemia pathway

Abstract

Activation of the Fanconi anemia (FA) DNA damage-response pathway results in the monoubiquitination of FANCD2, which is regulated by the nuclear FA core ubiquitin ligase complex. A FANCD2 protein sequence-based homology search facilitated the discovery of FANCI, a second monoubiquitinated component of the FA pathway. Biallelic mutations in the gene coding for this protein were found in cells from four FA patients, including an FA-I reference cell line.

The Fanconi anemia ID2 complex: Dueling saxes at the crossroads

“…10 In an alternative strategy, Sims and colleagues performed a BLAST search using the conserved amino acid sequence flanking the site of FANCD2 monoubiquitination K561, LVIRK, to identify proteins with similar monoubiquitination 'consensus' sequences. 9 A highly similar sequence -LVLRK -was uncovered in the uncharacterized protein KIAA1794, which, upon further examination, displayed approximately 40% sequence similarity within the regions surrounding KIAA1794 K523 and FANCD2 K561. 9 KIAA1794/FANCI was shown to undergo DNA damage-inducible monoubiquitination, and, importantly, this monoubiquitination was dependent on both the presence and monoubiquitination of FANCD2.…”

“…[8][9][10] Using a 2-step genome-wide linkage approach with 4 genetically informative families, Dorsman and colleagues identified 4 candidate regions encompassing 39.4 Mb and comprising 351 genes. The sequencing of several candidate DNA repair genes failed to reveal sequence alterations.…”

The ubiquitin landscape at DNA double-strand breaks

“…FancD2 ubiquitylation occurs in S phase in response to phosphorylation by the Rad3-related PIKK, ataxia telangiectasia and Rad3 related (ATR; Andreassen et al, 2004). Monoubiquitylation is critical for FancD2 and FancI localization to DSBs and chromatin association (Meetei et al, 2004;Wang et al, 2004;Sims et al, 2007;Smogorzewska et al, 2007). Though it is not clear how ubiquitylation controls Fanconi pathway activity, a carboxy-terminal FancD2-ubiquitin fusion protein strongly associated with DSBs and chromatin, whereas a fusion containing the Ile44Ala mutation in ubiquitin did not.…”

FANCD2 Western blot as a diagnostic tool for Brazilian patients with Fanconi anemia

“…Following DNA damage, the core complex is required for monoubiquitination of FANCD2, which is the central protein of FA/BRCA pathway. Studies by Smogorzewska et al (14) and Sims et al (29) suggest that previous monoubiquitination of FANCI is important for subsequent FANCD2 monoubiquitination. The activated isoform of FANCD2 (FANCD2L) is targeted to the nuclear foci where it functions in concert with BRCA1/BRCA2/RAD51 at the sites of DNA damage and repair (23,25,37).…”

“…FANCD2 is the central protein that connects the FA/BRCA pathway to the homologous recombination-mediated DNA repair (18,19,23,(25)(26)(27)(28). The recently identified FANCI protein associates with FANCD2 and is the second monoubiquitinated component of the FA pathway (14,29).…”