The Fanconi anaemia group G gene FANCG is identical with Xrcc9
ABSTRACT Fanconi anemia (FA) is an autosomal recessive disease with diverse clinical symptoms including developmental anomalies, bone marrow failure and early occurrence of malignancies. In addition to spontaneous chromosome instability, FA cells exhibit cell cycle disturbances and hypersensitivity to cross-linking agents. Eight complementation groups (A-H) have been distinguished, each group possibly representing a distinct FA gene. The genes mutated in patients of complementation groups A (FANCA; refs 4,5) and C (FANCC; ref. 6) have been identified, and FANCD has been mapped to chromosome band 3p22-26 (ref. 7). An additional FA gene has recently been mapped to chromosome 9p (ref. 8). Here we report the identification of the gene mutated in group G, FANCG, on the basis of complementation of an FA-G cell line and the presence of pathogenic mutations in four FA-G patients. We identified the gene as human XRCC9, a gene which has been shown to complement the MMC-sensitive Chinese hamster mutant UV40, and is suspected to be involved in DNA post-replication repair or cell cycle checkpoint control. The gene is localized to chromosome band 9p13 (ref. 9), corresponding with a known localization of an FA gene.
- SourceAvailable from: Juan A Bueren
DNA Repair and Human Health, 10/2011; , ISBN: 978-953-307-612-6
- "Only those cells complemented with FANCC grew after MMC exposure, allowing the identification of the defective gene in these patients. Similar approaches, together with positional cloning and linkage analysis, allowed the identification of other protein members of the so called " FA core complex " , which included FANCA, FANCG, FANCF and FANCE    . Although the description of FANCD2 and its activation by monoubiquitination after DNA damage linked FA with DNA repair, the confirmation of the involvement of the FA pathway in DNA repair and its link to homologous recombination occurred in 2002, when BRCA2 was identified as the FANCD1 gene. "
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- "The identification of the first FA genes (FANCA, -C, -F, and -G) provided little insight into the molecular function of the FA pathway , since these genes have no apparent functional domains in their primary polypeptide sequence    . Therefore the positional cloning and identification of the FA gene FANCD2 was a major milestone in FA research  . "
ABSTRACT: The hereditary genetic disorder Fanconi anemia (FA) belongs to the heterogeneous group of diseases associated with defective DNA damage repair. Recently, several reviews have discussed the FA pathway and its molecular players in the context of genome maintenance and tumor suppression mechanisms [H. Joenje, K.J. Patel, The emerging genetic and molecular basis of Fanconi anaemia, Nat. Rev. Genet. 2 (2001) 446-457; W. Wang, Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins, Nat. Rev. Genet. 8 (2007) 735-748; L.J. Niedernhofer, A.S. Lalai, J.H. Hoeijmakers, Fanconi anemia (cross)linked to DNA repair, Cell 123 (2005) 1191-1198; K.J. Patel, Fanconi anemia and breast cancer susceptibility, Nat. Genet. 39 (2007) 142-143]. This review assesses the influence of post-translational modification by ubiquitin. We review and extract the key features of the enzymatic cascade required for the monoubiquitylation of the FANCD2/FANCI complex and attempt to include recent findings into a coherent mechanism. As this part of the FA pathway is still far from fully understood, we raise several points that must be addressed in future studies.DNA Repair 05/2009; 8(4):430-5. DOI:10.1016/j.dnarep.2009.01.019 · 3.36 Impact Factor
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- "FANCG required for BRCA2–FANCD2–XRCC3 interactions JB Wilson et al 2006), and we can also now report the co-precipitation of FANCD2 with both FANCG and XRCC3 in hamster and human cells (Figure 5, lanes 1, 4 and 5). While a direct interaction between FANCG and FANCD2 has not been reported, both interact directly with BRCA2 (de Winter et al., 1998; Hussain et al., 2003, 2004). Each of these four proteins can therefore be co-precipitated with the other three, suggesting that they exist together in a single protein complex (D1-D2- G-X3). "
ABSTRACT: Fanconi anemia (FA) is a human disorder characterized by cancer susceptibility and cellular sensitivity to DNA crosslinks and other damages. Thirteen complementation groups and genes are identified, including BRCA2, which is defective in the FA-D1 group. Eight of the FA proteins, including FANCG, participate in a nuclear core complex that is required for the monoubiquitylation of FANCD2 and FANCI. FANCD2, like FANCD1/BRCA2, is not part of the core complex, and we previously showed direct BRCA2-FANCD2 interaction using yeast two-hybrid analysis. We now show in human and hamster cells that expression of FANCG protein, but not the other core complex proteins, is required for co-precipitation of BRCA2 and FANCD2. We also show that phosphorylation of FANCG serine 7 is required for its co-precipitation with BRCA2, XRCC3 and FANCD2, as well as the direct interaction of BRCA2-FANCD2. These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3). Cells that fail to express either phospho-Ser7-FANCG, or full length BRCA2 protein, lack the interactions amongst the four component proteins. A role for D1-D2-G-X3 in homologous recombination repair (HRR) is supported by our finding that FANCG and the RAD51-paralog XRCC3 are epistatic for sensitivity to DNA crosslinking compounds in DT40 chicken cells. Our findings further define the intricate interface between FANC and HRR proteins in maintaining chromosome stability.Oncogene 07/2008; 27(26):3641-52. DOI:10.1038/sj.onc.1211034 · 8.56 Impact Factor