A physical complex of the Fanconi anemia proteins FANCG/XRCC9 and FANCA

Waisfisz, Quinten; Winter, Johan P. de; Kruyt, Frank A.E.; Groot, Jan de; Weel, Laura van der; Dijkmans, Lonneke M.; Zhi, Yu; Arwert, Fré; Scheper, Rik J.; Youssoufian, Hagop; Hoatlin, Maureen E.; Joenje, Hans

doi:10.1073/pnas.96.18.10320

Cited by 143 publications

(122 citation statements)

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“…Recent work has found the FANCE, FANCF, FANCG, and FANCL proteins in the complex as well (31)(32)(33)(34). A large complex is suggested by our recent work (35), and binding does not occur in any of the complementation groups except the FA-D1, D2, I, and J groups (7).…”

mentioning

confidence: 69%

Phosphorylation of Fanconi Anemia (FA) Complementation Group G Protein, FANCG, at Serine 7 Is Important for Function of the FA Pathway

Qiao¹,

Mi²,

Wilson

et al. 2004

Journal of Biological Chemistry

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Fanconi anemia (FA) 1 is a genetic disease of cancer susceptibility marked by congenital defects, bone marrow failure, and myeloid leukemia (1-4). To date at least 11 complementation groups have been defined (5-7). Eight genes have been cloned (8 -17). However, the gene products resemble no known proteins and have few identifiable functional protein motifs. One exception is the recently cloned FANCL gene, which contains the ubiquitin ligase motif. In addition, the FANCD1 gene has been identified as BRCA2, one of the familial breast cancer genes.Cells derived from patients with the FA exhibit characteristic hypersensitivity caused by DNA cross-linking agents and generalized decreased survival (18 -22). However, no defined biochemical mechanism for this hypersensitivity has been elucidated, although studies have implicated cytokine dysregulation, excessive, oxidative damage, defects in DNA repair, and lack of cell cycle control (23-27). Patient and cellular phenotypes across all the complementation groups are similar, suggesting an inter-relatedness or cooperativity between the FA proteins.This cooperativity has been borne out by work we have done in showing binding of FANCA and FANCC in a protein complex in both nucleus and cytoplasm (28 -30). Recent work has found the FANCE, FANCF, FANCG, and FANCL proteins in the complex as well (31-34). A large complex is suggested by our recent work (35), and binding does not occur in any of the complementation groups except the FA-D1, D2, I, and J groups (7).One clue to FA function lies in the study of the FANCA protein, which contains a classic bipartite nuclear localization signal and is phosphorylated. Generally, FANCA nuclear localization, phosphorylation, and binding to FANCC are abolished in all complementation groups except the FA-D1 and D2 groups (28 -30, 33). This suggests that a nuclear event is critical to the normal function of the FA proteins, and the aberrant proteins in the FA-D groups may have a role downstream of the FA complex in the nucleus. However, some have found FANCA point mutants that are expressed, translocated to the nucleus, and are phosphorylated to some extent. Some of these mutants are of intermediate MMC sensitivity (36).Over the years, little information has been found that addresses the regulation of the FA proteins. mRNA or protein levels change little in response to DNA damage or the cell cycle. Our recent work has revealed that at least a subset of the FA proteins resides in the nucleus bound to chromatin, where increased protein binding occurs in response to DNA damage (37). One of the non-core complex FA proteins, FANCD2, becomes monoubiquitinated in response to DNA damage (38).In addition, we have shown during the cell cycle that the FA proteins detach from chromatin during mitosis, and FANCG becomes phosphorylated while remaining part of the complex (37). One group has demonstrated that FANCG has a isoform seen in asynchronous cells that is phosphatase sensitive (39).In this paper we report the identification of a phosphopeptide from ...

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confidence: 69%

Phosphorylation of Fanconi Anemia (FA) Complementation Group G Protein, FANCG, at Serine 7 Is Important for Function of the FA Pathway

Qiao¹,

Mi²,

Wilson

et al. 2004

Journal of Biological Chemistry

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“…We have observed interdependence of protein signals in immunoblots in other patients of both FA-A and FA-G complementation groups. 14 Of 35 assigned German families, nine belong to complementation group FA-G making this the second largest group in Germany after FA-A (68%). The 313G → T mutation accounts for 44% of the alleles in German FA-G patients and is clearly due to a founder effect.…”

Section: Discussionmentioning

confidence: 99%

“…However, several studies have shown that FANCG is found in the cells as a nuclear complex with the FANCA protein. 14,15 Pathogenic mutations in FANCG were previously reported in four FA-G patients, we report here further mutations in 16 FA-G patients, including common German and Turkish founder mutations.…”

Section: Introductionmentioning

confidence: 97%

Spectrum of mutations in the Fanconi anaemia group G gene, FANCG/XRCC9

Demuth

Wlodarski

Tipping³

et al. 2000

Eur J Hum Genet

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FANCG was the third Faconi anaemia gene identified and proved to be identical to the previously cloned XRCC9 gene. We present the pathogenic mutations and sequence variants we have so far identified in a panel of FA-G patients. Mutation screening was performed by PCR, single strand conformational polymorphism analysis and protein truncation tests. Altogether 18 mutations have been determined in 20 families -97% of all expected mutant alleles. All mutation types have been found, with the exception of large deletions, the large majority is predicted to lead to shortened proteins. One stop codon mutation, E105X, has been found in several German patients and this founder mutation accounts for 44% of the mutant FANCG alleles in German FA-G patients. Comparison of clinical phenotypes shows that patients homozygous for this mutation have an earlier onset of the haematological disorder than most other FA-G patients. The mouse Fancg sequence was established in order to evaluate missense mutations. A putative missense mutation, L71P, in a possible leucine zipper motif may affect FANCG binding of FANCA and seems to be associated with a milder clinical phenotype.

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“…Together, our results suggest that the FANCA-FANCG interaction may occur through intermolecular disulfide linkage(s) in a oxidative damage-dependent manner. protein complex (4,14,27), and FANCG (XRCC9) protein is required for binding of the FANCA and FANCC proteins (4,14), suggesting that FANC proteins form a large multiprotein complex that may be necessary for their function in damage signaling and repair. In this study we examined the interaction of FANC proteins in response to oxidative stress.…”

Section: Fanca-fancg Interaction Is Significantly Enhanced In Responsmentioning

confidence: 99%

Oxidative Stress/Damage Induces Multimerization and Interaction of Fanconi Anemia Proteins

Park

Ciccone

Beck

et al. 2004

Journal of Biological Chemistry

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Fanconi anemia (FANC) is a heterogeneous genetic disorder characterized by a hypersensitivity to DNAdamaging agents, chromosomal instability, and defective DNA repair. Eight FANC genes have been identified so far, and five of them (FANCA, -C, -E, -F, and -G) assemble in a multinuclear complex and function at least in part in a complex to activate FANCD2 by monoubiquitination. Here Fanconi anemia (FANC) 1 is an autosomal recessive disorder characterized by chromosomal instability and defective DNA repair, and FANC-deficient cells exhibit extreme sensitivity toward oxygen and DNA-cross-linking agents such as diepoxybutane and mitomycin C (1-3). The gene products of eight complementation groups of FANC have been identified and cloned (FANCA, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, and FANCL) (1-3). Mutations in any of the eight different genes lead to FANC disease, a degree of genetic heterogeneity comparable with that of other DNA repair disorders, suggesting that each group represents a distinct protein.FANCA and FANCG proteins are part of a large nuclear protein complex required for their function, and the disruption of this complex results in the specific cellular and clinical phenotype common to most FANC complementation groups (4). FANCA gene encodes a 162-kDa phosphoprotein and its phosphorylation correlated with FANCA/FANCC protein accumulation in the nucleus (5). FANCA mutant cells isolated from a FANC patient were defective in their phosphorylation and failed to bind to FANCC. Furthermore, a mutant FANCA protein failed to complement the mitomycin C (MMC) sensitivity of FANCAϪ/Ϫ cells, suggesting that FANCA phosphorylation may be involved in FANCC interaction, nuclear localization of FANCA, or its function in cross-link repair. FANCG gene encodes a 65-kDa protein that has been identified as human XRCC9. XRCC9 (FANCG) complements the Chinese hamster ovary mutant UV-40 cell line that is hypersensitive to UV, ionizing radiation, simple alkylating agents, and DNA-crosslinking agents (6, 7). The mutant cells also show a high level of spontaneous chromosomal aberrations that can be fully corrected by introduction of XRCC9 cDNA transformants (7). The possibility of the involvement of FANC proteins in DNA repair was strengthened by recent findings on the interaction of FANCD1 with BRCA1 following DNA damage (8). FANCD1 is identical to BRCA2 gene and is unique among FANC genes in that it is essential for the formation of Rad51 foci in response to ionizing radiation (9), suggesting that it may be involved in homologous recombination-mediated strand break repair.Cells lacking FANC gene showed a hypersensitive phenotype following H 2 O 2 treatment, suggesting a role for FANC proteins in redox signaling and repair of oxidative DNA damages (Refs. 10 -13 and data not shown). Interaction between FANCA and FANCG was well established by coimmunoprecipitation, cellular localization, and yeast two-hybrid analysis (4, 14 -18). Although the detailed functions of FANC proteins have yet to be determined, there is a growi...

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A physical complex of the Fanconi anemia proteins FANCG/XRCC9 and FANCA

Cited by 143 publications

References 35 publications

Phosphorylation of Fanconi Anemia (FA) Complementation Group G Protein, FANCG, at Serine 7 Is Important for Function of the FA Pathway

Phosphorylation of Fanconi Anemia (FA) Complementation Group G Protein, FANCG, at Serine 7 Is Important for Function of the FA Pathway

Spectrum of mutations in the Fanconi anaemia group G gene, FANCG/XRCC9

Oxidative Stress/Damage Induces Multimerization and Interaction of Fanconi Anemia Proteins

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