Positional Cloning of a Novel Fanconi Anemia Gene, FANCD2

Timmers, Cynthia; Taniguchi, Toshiyasu; Hejna, James; Reifsteck, Carol A.; Lucas, Lora; Bruun, Donald A.; Thayer, Mathew J.; Cox, Benjamin F.; Olson, Susan B.; D’Andrea, Alan D.; Moses, Robb E.; Grompe, Markus

doi:10.1016/s1097-2765(01)00172-1

Cited by 363 publications

(290 citation statements)

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“…Cells derived from FA patients are characterized by chromosomal instability and hypersensitivity to ICL-inducing agents and, in at least some cases, to ionizing radiation (IR) (Carreau et al, 1999;Garcia-Higuera et al, 2001;Gatti, 2001;Digweed et al, 2002). The disease has a high degree of heterogeneity, with 11 known complementation groups (FA-A, B, C, D1, D2, E, F, G, I, J and K) (Levitus et al, 2003) and eight genes (FANCA, C, D1/BRCA2, D2, E, F, G, L) cloned thus far (Strathdee et al, 1992;Lo Len Foe et al, 1996; The Fanconi anaemia/breast cancer Consortium, 1996;de Winter et al, 1998de Winter et al, , 2000aTimmers et al, 2001;Howlett et al, 2002;Meetei et al, 2003). Most of the FA proteins associate in the FA core complex, which is required for the monoubiquitination of FANCD2, resulting in localization of FANCD2 in nuclear foci containing BRCA1 and BRCA2/FANCD1.…”

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confidence: 99%

Human SNM1B is required for normal cellular response to both DNA interstrand crosslink-inducing agents and ionizing radiation

2004

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DNA interstrand crosslinks (ICLs) are critical lesions for the mammalian cell since they affect both DNA strands and block transcription and replication. The repair of ICLs in the mammalian cell involves components of different repair pathways such as nucleotide-excision repair and the double-strand break/homologous recombination repair pathways. However, the mechanistic details of mammalian ICL repair have not been fully delineated. We describe here the complete coding sequence and the genomic organization of hSNM1B, one of at least three human homologs of the Saccharomyces cerevisiae PSO2 gene. Depletion of hSNM1B by RNA interference rendered cells hypersensitive to ICL-inducing agents. This requirement for hSNM1B in the cellular response to ICL has been hypothesized before but never experimentally verified. In addition, siRNA knockdown of hSNM1B rendered cells sensitive to ionizing radiation, suggesting the possibility of hSNM1B involvement in homologous recombination repair of double-strand breaks arising as intermediates of ICL repair. Monoubiquitination of FANCD2, a key step in the FANC/BRCA pathway, is not affected in hSNM1B-depleted HeLa cells, indicating that hSNM1B is probably not a part of the Fanconi anemia core complex. Nonetheless, similarities in the phenotype of hSNM1B-depleted cells and cultured cells from patients suffering from Fanconi anemia make hSNM1B a candidate for one of the as yet unidentified Fanconi anemia genes not involved in monoubiquitination of FANCD2.

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Section: Introductionmentioning

confidence: 99%

Human SNM1B is required for normal cellular response to both DNA interstrand crosslink-inducing agents and ionizing radiation

2004

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“…3 A recent survey of cancer incidence in 145 FA patients reported nine cases of myeloid leukemia with a median age-of-onset of 11.3 years, and a ratio of observed to expected cases of 785. 4 Complementation analysis by cell fusion and correction of crosslinker hypersensitivity has delineated at least eight complementation groups; FA-A, B, C, D1, D2, E, F, G, 5 six genes have been cloned, FANCA, C, D2, E, F, G, [6][7][8][9][10][11][12] and a recent report has shown biallelic inactivation of BRCA2 in FA-D1 cell lines. 13 Since the incidence of AML is highly elevated in FA patients, it is possible that inherited or acquired mutations in the FA genes contribute to the etiology of sporadic AML.…”

Section: Introductionmentioning

confidence: 99%

Deletion and reduced expression of the Fanconi anemia FANCA gene in sporadic acute myeloid leukemia

et al. 2004

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Fanconi anemia (FA) is an autosomal recessive chromosomal instability disorder caused by mutations in one of seven known genes (FANCA,C,D2,E,F,G and BRCA2). Mutations in the FANCA gene are the most prevalent, accounting for two-thirds of FA cases. Affected individuals have greatly increased risks of acute myeloid leukemia (AML). This raises the question as to whether inherited or acquired mutations in FA genes might be involved in the development of sporadic AML. Quantitative fluorescent PCR was used to screen archival DNA from sporadic AML cases for FANCA deletions, which account for 40% of FANCA mutations in FA homozygotes. Four heterozygous deletions were found in 101 samples screened, which is 35-fold higher than the expected population frequency for germline FANCA deletions (Po0.0001). Sequencing FANCA in the AML samples with FANCA deletions did not detect mutations in the second allele and there was no evidence of epigenetic silencing by hypermethylation. However, real-time quantitative PCR analysis in these samples showed reduced expression of FANCA compared to nondeleted AML samples and to controls. These findings suggest that gene deletions and reduced expression of FANCA may be involved in the promotion of genetic instability in a subset of cases of sporadic AML.

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“…FANCD2 is thought to play a central role in the FA/BRCA pathway and is well conserved among different multicellular eukaryotic species, whereas the majority of FA core complex genes do not exist in many lower eukaryotes. 22,23 Interestingly, there is some evidence that patients with FANCD2 mutations have earlier onset and more rapid progression of hematologic manifestations. 24 It is also noteworthy that all the FANCD2 mutations identified in human patients are hypomorphic, whereas Fancd2 Ϫ/Ϫ mice have null mutations.…”

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Fancd2 −/− mice have hematopoietic defects that can be partially corrected by resveratrol

Zhang

Marquez-Loza

Eaton

et al. 2010

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Progressive bone marrow failure is a major cause of morbidity and mortality in human Fanconi Anemia patients. In an effort to develop a Fanconi Anemia murine model to study bone marrow failure, we found that Fancd2 ؊/؊ mice have readily measurable hematopoietic defects. Fancd2 deficiency was associated with a significant decline in the size of the c-Kit ؉ Sca-1 ؉ Lineage ؊ (KSL) pool and reduced stem cell repopulation and spleen colony-forming capacity. Fancd2 ؊/؊ KSL cells showed an abnormal cell cycle status and loss of quiescence. In addition, the supportive function of the marrow microenvironment was compromised in Fancd2 ؊/؊ mice. Treatment with Sirt1-mimetic and the antioxidant drug, resveratrol, maintained Fancd2 ؊/؊ KSL cells in quiescence, improved the marrow microenvironment, partially corrected the abnormal cell cycle status, and significantly improved the spleen colony-forming capacity of Fancd2 ؊/؊ bone marrow cells. We conclude that Fancd2 ؊/؊ mice have readily quantifiable hematopoietic defects, and that this model is well suited for pharmacologic screening studies. IntroductionFanconi anemia (FA) is a rare, autosomal, recessive genetic disorder associated with severe birth defects, cancer predisposition, and bone marrow failure. Thirteen causative genes (FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG/XRCC9, FANCI, FANCL/PHF9/Pog, FANCJ/BRIP1/BACH1, FANCM/Hef, and FANCN/ PALB2) have been identified and cloned to date, and the encoded proteins are believed to work together in a common DNA damageresponse pathway to maintain genomic integrity and protect the genome from DNA damage induced by cross-linking agents. 1,2 Although deficiency in DNA cross-link repair renders all FA cells susceptible to cross-linking agents, bone marrow is the most affected organ system. Mutations in any of the different FA genes almost universally lead to bone marrow failure, which is the primary cause of mortality in FA. 3 The pathogenesis of bone marrow failure in FA remains elusive. Mutations in several genes involved in DNA damage repair, including Atr, XPD, and Ercc1, caused either hematopoietic stem cell (HSC) loss or impaired HSC function under conditions of stress. [4][5][6] These studies suggest that the maintenance of genome integrity is critical for HSC survival and function. However, the extent to which genotoxicity, resulting from impaired DNA damage repair, contributes to bone marrow failure in FA is unclear. 7 Other pathways associated with hematopoietic failure, such as altered cytokine signaling, may also contribute to FA pathogenesis. 8,9 For example, levels of proapoptotic cytokines tumor necrosis factor-␣ (TNF-␣) and interferon-␥ (IFN-␥) are elevated in FA lymphocytes, bone marrow cells, and FA patient serum samples. 10-12 FA bone marrow cells (at least of the C complementation group) are also hypersensitive to these cytokines and undergo apoptosis when exposed to even low levels of them. [13][14][15] To better understand FA, multiple murine knockout models, includingand Fancl Ϫ/Ϫ m...

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Positional Cloning of a Novel Fanconi Anemia Gene, FANCD2

Abstract: a molecular complex with primarily nuclear localization (Kupfer et al., 1997; Garcia-Higuera et al., 1999; Waisfisz et al., 1999a). FANCC also localizes to the cytoplasm,

Cited by 363 publications

References 33 publications

Human SNM1B is required for normal cellular response to both DNA interstrand crosslink-inducing agents and ionizing radiation

Human SNM1B is required for normal cellular response to both DNA interstrand crosslink-inducing agents and ionizing radiation

Deletion and reduced expression of the Fanconi anemia FANCA gene in sporadic acute myeloid leukemia

Fancd2 −/− mice have hematopoietic defects that can be partially corrected by resveratrol

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