A Novel BTB/POZ Transcriptional Repressor Protein Interacts With the Fanconi Anemia Group C Protein and PLZF

Blood ◽  
1999 ◽  
Vol 94 (11) ◽  
pp. 3737-3747 ◽  
Author(s):  
Maureen E. Hoatlin ◽  
Yu Zhi ◽  
Helen Ball ◽  
Kirsten Silvey ◽  
Ari Melnick ◽  
...  
Keyword(s):  
Fanconi Anemia ◽  
Transcriptional Repression ◽  
Cancer Susceptibility ◽  
Bone Marrow Failure ◽  
Severe Disease ◽  
Transcriptional Repressor ◽  
Interaction Domain ◽  
C Protein ◽  
Amino Terminal ◽  
Anemia Group

Fanconi anemia (FA) is an autosomal recessive cancer susceptibility syndrome. The phenotype includes developmental defects, bone marrow failure, and cell cycle abnormalities. At least eight complementation groups (A-H) exist, and although three of the corresponding complementation group genes have been cloned, they lack recognizable motifs, and their functions are unknown. We have isolated a binding partner for the Fanconi anemia group C protein (FANCC) by yeast two-hybrid screening. We show that the novel gene, FAZF, encodes a 486 amino acid protein containing a conserved amino terminal BTB/POZ protein interaction domain and three C-terminal Krüppel-like zinc fingers. FAZF is homologous to the promyelocytic leukemia zinc finger (PLZF) protein, which has been shown to act as a transcriptional repressor by recruitment of nuclear corepressors (N-CoR, Sin3, and HDAC1 complex). Consistent with a role in FA, BTB/POZ-containing proteins have been implicated in oncogenesis, limb morphogenesis, hematopoiesis, and proliferation. We show that FAZF is a transcriptional repressor that is able to bind to the same DNA target sequences as PLZF. Our data suggest that the FAZF/FANCC interaction maps to a region of FANCC deleted in FA patients with a severe disease phenotype. We also show that FAZF and wild-type FANCC can colocalize in nuclear foci, whereas a patient-derived mutant FANCC that is compromised for nuclear localization cannot. These results suggest that the function of FANCC may be linked to a transcriptional repression pathway involved in chromatin remodeling.

A Novel BTB/POZ Transcriptional Repressor Protein Interacts With the Fanconi Anemia Group C Protein and PLZF

Blood ◽  
1999 ◽  
Vol 94 (11) ◽  
pp. 3737-3747 ◽  
Author(s):  
Maureen E. Hoatlin ◽  
Yu Zhi ◽  
Helen Ball ◽  
Kirsten Silvey ◽  
Ari Melnick ◽  
...  
Keyword(s):  
Fanconi Anemia ◽  
Transcriptional Repression ◽  
Cancer Susceptibility ◽  
Bone Marrow Failure ◽  
Severe Disease ◽  
Transcriptional Repressor ◽  
Interaction Domain ◽  
C Protein ◽  
Amino Terminal ◽  
Anemia Group

Abstract Fanconi anemia (FA) is an autosomal recessive cancer susceptibility syndrome. The phenotype includes developmental defects, bone marrow failure, and cell cycle abnormalities. At least eight complementation groups (A-H) exist, and although three of the corresponding complementation group genes have been cloned, they lack recognizable motifs, and their functions are unknown. We have isolated a binding partner for the Fanconi anemia group C protein (FANCC) by yeast two-hybrid screening. We show that the novel gene, FAZF, encodes a 486 amino acid protein containing a conserved amino terminal BTB/POZ protein interaction domain and three C-terminal Krüppel-like zinc fingers. FAZF is homologous to the promyelocytic leukemia zinc finger (PLZF) protein, which has been shown to act as a transcriptional repressor by recruitment of nuclear corepressors (N-CoR, Sin3, and HDAC1 complex). Consistent with a role in FA, BTB/POZ-containing proteins have been implicated in oncogenesis, limb morphogenesis, hematopoiesis, and proliferation. We show that FAZF is a transcriptional repressor that is able to bind to the same DNA target sequences as PLZF. Our data suggest that the FAZF/FANCC interaction maps to a region of FANCC deleted in FA patients with a severe disease phenotype. We also show that FAZF and wild-type FANCC can colocalize in nuclear foci, whereas a patient-derived mutant FANCC that is compromised for nuclear localization cannot. These results suggest that the function of FANCC may be linked to a transcriptional repression pathway involved in chromatin remodeling.

Detection of somatic mosaicism and classification of Fanconi anemia patients by analysis of the FA/BRCA pathway

Blood ◽  
2005 ◽  
Vol 105 (3) ◽  
pp. 1329-1336 ◽  
Author(s):  
Jean Soulier ◽  
Thierry Leblanc ◽  
Jérôme Larghero ◽  
Hélène Dastot ◽  
Akiko Shimamura ◽  
...  
Keyword(s):  
Fanconi Anemia ◽  
Cancer Susceptibility ◽  
Bone Marrow Failure ◽  
Somatic Mosaicism ◽  
Chromosome Breakage ◽  
Peripheral Blood Lymphocytes ◽  
Specific Analysis ◽  
Number Of Patients ◽  
Chromosome Fragility

AbstractFanconi anemia (FA) is characterized by congenital abnormalities, bone marrow failure, chromosome fragility, and cancer susceptibility. Eight FA-associated genes have been identified so far, the products of which function in the FA/BRCA pathway. A key event in the pathway is the monoubiquitination of the FANCD2 protein, which depends on a multiprotein FA core complex. In a number of patients, spontaneous genetic reversion can correct FA mutations, leading to somatic mosaicism. We analyzed the FA/BRCA pathway in 53 FA patients by FANCD2 immunoblots and chromosome breakage tests. Strikingly, FANCD2 monoubiquitination was detected in peripheral blood lymphocytes (PBLs) in 8 (15%) patients. FA reversion was further shown in these patients by comparison of primary fibro-blasts and PBLs. Reversion was associated with higher blood counts and clinical stability or improvement. Once constitutional FANCD2 patterns were determined, patients could be classified based on the level of FA/BRCA pathway disruption, as “FA core” (upstream inactivation; n = 47, 89%), FA-D2 (n = 4, 8%), and an unidentified downstream group (n = 2, 4%). FA-D2 and unidentified group patients were therefore relatively common, and they had more severe congenital phenotypes. These results show that specific analysis of the FA/BRCA pathway, combined with clinical and chromosome breakage data, allows a comprehensive characterization of FA patients.

scholarly journals Cytogenetic diepoxybutane sensitivity in Serbian children with Fanconi anemia

2006 ◽  
Vol 58 (4) ◽  
pp. 215-219
Author(s):  
Sanja Cirkovic ◽  
Marija Guc-Scekic ◽  
Dragana Vujic ◽  
D. Micic
Keyword(s):  
Fanconi Anemia ◽  
Cancer Susceptibility ◽  
Bone Marrow Failure ◽  
Alkylating Agents ◽  
Chromosome Breakage ◽  
Child Health Care ◽  
Bone Marrow Failure Syndromes ◽  
Mother And Child Health ◽  
Mother And Child ◽  
And Child Health

Fanconi anemia (FA) is an inherited disorder with aplastic anemia, cancer susceptibility, and hypersensitivity to alkylating agents such as diepoxybutane (DEB). The DEB test is used to screen for FA among patients with bone marrow failure syndromes (BMFS). From February of 2004 to May of 2006, 29 children with BMFS were diagnosed and treated at the Mother and Child Health Care Institute of Serbia (MCHIS). In the examined group, five out of 29 patients (17.2%) were found to have increased DEB-induced chromosome breakage (0.58-2.15 vs. 0.00-0.20 breaks/cell; p<0.001) with no overlap. Our results suggest the importance of this analysis for differential diagnosis and adequate therapy of FA among patients with BMFS.

scholarly journals DNA Repair: Exploiting the Fanconi Anemia Pathway As a Potential Therapeutic Target

2011 ◽  
pp. 453-465 ◽  
Author(s):  
T. HUCL ◽  
E. GALLMEIER
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Fanconi Anemia ◽  
Cancer Susceptibility ◽  
Synthetic Lethality ◽  
Bone Marrow Failure ◽  
Long Term Effects ◽  
Alternative Pathways ◽  
Repair Mechanisms ◽  
Relationship Of

DNA repair is an active cellular process to respond to constant DNA damage caused by metabolic processes and environmental factors. Since the outcome of DNA damage is generally adverse and long term effects may contribute to oncogenesis, cells have developed a variety of DNA repair mechanisms, which operate depending on the type of DNA damage inflicted. At least 15 Fanconi anemia (FA) proteins interact in a common pathway involved in homologous recombination. Inherited homozygous mutations in any of these FA genes cause a rare disease, Fanconi anemia, characterized by congenital abnormalities, progressive bone-marrow failure and cancer susceptibility. Heterozygous germline FA mutations predispose to various types of cancer. In addition, somatic FA mutations have been identified in diverse cancer types. Evidence exists that cells deficient in the FA pathway become dependent on alternative pathways for survival. Additional inhibition of such alternative pathways is thus expected to result in cell death, creating a relationship of synthetic lethality. Identifying these relationships can reveal yet unknown mechanisms of DNA repair and new targets for therapy.

scholarly journals The Fanconi Anemia Group C Protein Interacts with Uncoordinated 5A and Delays Apoptosis

PLoS ONE ◽  
2014 ◽  
Vol 9 (3) ◽  
pp. e92811 ◽  
Author(s):  
FengFei Huang ◽  
Manel Ben Aissa ◽  
Audrey Magron ◽  
Caroline C. Huard ◽  
Chantal Godin ◽  
...  
Keyword(s):  
Fanconi Anemia ◽  
C Protein ◽  
Anemia Group

scholarly journals Fanconi Anemia FANCG Protein in Mitigating Radiation- and Enzyme-Induced DNA Double-Strand Breaks by Homologous Recombination in Vertebrate Cells

2003 ◽  
Vol 23 (15) ◽  
pp. 5421-5430 ◽  
Author(s):  
Kazuhiko Yamamoto ◽  
Masamichi Ishiai ◽  
Nobuko Matsushita ◽  
Hiroshi Arakawa ◽  
Jane E. Lamerdin ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Fanconi Anemia ◽  
Cancer Susceptibility ◽  
Bone Marrow Failure ◽  
Chromosome Breakage ◽  
Breast Cancer Susceptibility ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Brca1 And Brca2 ◽  
Strand Breaks

ABSTRACT The rare hereditary disorder Fanconi anemia (FA) is characterized by progressive bone marrow failure, congenital skeletal abnormality, elevated susceptibility to cancer, and cellular hypersensitivity to DNA cross-linking chemicals and sometimes other DNA-damaging agents. Molecular cloning identified six causative genes (FANCA, -C, -D2, -E, -F, and -G) encoding a multiprotein complex whose precise biochemical function remains elusive. Recent studies implicate this complex in DNA damage responses that are linked to the breast cancer susceptibility proteins BRCA1 and BRCA2. Mutations in BRCA2, which participates in homologous recombination (HR), are the underlying cause in some FA patients. To elucidate the roles of FA genes in HR, we disrupted the FANCG/XRCC9 locus in the chicken B-cell line DT40. FANCG-deficient DT40 cells resemble mammalian fancg mutants in that they are sensitive to killing by cisplatin and mitomycin C (MMC) and exhibit increased MMC and radiation-induced chromosome breakage. We find that the repair of I-SceI-induced chromosomal double-strand breaks (DSBs) by HR is decreased ∼9-fold in fancg cells compared with the parental and FANCG-complemented cells. In addition, the efficiency of gene targeting is mildly decreased in FANCG-deficient cells, but depends on the specific locus. We conclude that FANCG is required for efficient HR-mediated repair of at least some types of DSBs.

scholarly journals The effect of the Fanconi anemia polypeptide, FAC, upon p53 induction and G2 checkpoint regulation

Blood ◽  
1996 ◽  
Vol 88 (3) ◽  
pp. 1019-1025 ◽  
Author(s):  
GM Kupfer ◽  
AD D'Andrea
Keyword(s):  
Cell Cycle ◽  
Cell Line ◽  
Cell Lines ◽  
Fanconi Anemia ◽  
Cancer Susceptibility ◽  
Bone Marrow Failure ◽  
Alkylating Agents ◽  
P53 Pathway ◽  
G2 Checkpoint ◽  
G2 Phase

Fanconi anemia (FA) is an autosomal recessive disease marked by developmental defects, bone marrow failure, and cancer susceptibility. FA cells are hypersensitive to DNA cross-linking and alkylating agents and accumulate in the G2 phase of the cell cycle in response to these agents. FA cells also display genomic instability, suggesting a possible defect in the p53 pathway. To test the effect of heterologous expression of FAC cDNA on drug-induced cytotoxicity, G2 accumulation, and p53 induction in FA cells, we compared two isogenic FA cell lines: HSC536N (mock), a FA type C cell line sensitive to mitomycin C (MMC), and the same cell line transfected (corrected) with wild-type FAC cDNA (HSC536N [+FAC]). HSC536N (+FAC) cells showed a 30-fold increase in resistance to MMC concentration. Similarly, increases in resistance were observed following exposure to cisplatin, carboplatin, and cyclophosphamide. In addition, HSC536N (+FAC) cells showed a twofold lower G2 accumulation following MMC treatment. To analyze the possible interaction of FAC with the p53 pathway, we analyzed p53 induction in mock and corrected cell lines following exposure to MMC. HSC536N (mock) cells induced p53 at lower MMC concentrations than HSC536N (corrected). Caffeine, a known G2 checkpoint inhibitor, not only inhibited G2 accumulation seen in both cell lines but also caused the resistant HSC536N (+FAC) to become as sensitive to MMC as HSC536N (mock) cell line. We conclude that the FAC protein has a specific cytoprotective effect and may function as a cell cycle regulator of the G2 phase of the cell cycle.

scholarly journals Regulation of the Fanconi Anemia Group C Protein through Proteolytic Modification

2003 ◽  
Vol 279 (6) ◽  
pp. 4713-4720 ◽  
Author(s):  
Isabelle Brodeur ◽  
Isabelle Goulet ◽  
Cédric S. Tremblay ◽  
Chantal Charbonneau ◽  
Marie-Chantal Delisle ◽  
...  
Keyword(s):  
Fanconi Anemia ◽  
C Protein ◽  
Anemia Group

A 20-year perspective on the International Fanconi Anemia Registry (IFAR)

Blood ◽  
2003 ◽  
Vol 101 (4) ◽  
pp. 1249-1256 ◽  
Author(s):  
David I. Kutler ◽  
Bhuvanesh Singh ◽  
Jaya Satagopan ◽  
Sat Dev Batish ◽  
Marianne Berwick ◽  
...  
Keyword(s):  
Fanconi Anemia ◽  
Cancer Susceptibility ◽  
Bone Marrow Failure ◽  
Cell Cycle Control ◽  
Univariate Analysis ◽  
Autosomal Recessive Disorder ◽  
Brca1 And Brca2 ◽  
Hematopoietic Stem ◽  
Number Of Patients ◽  
Significant Difference

Fanconi anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA cross-linking agents and cancer predisposition. Recent evidence for the interactions of ataxia-telangiectasia mutated protein ATM and breast cancer susceptibility proteins BRCA1 and BRCA2 (identified as FANCD1) with other known FA proteins suggests that FA proteins have a significant role in DNA repair/recombination and cell cycle control. The International Fanconi Anemia Registry (IFAR), a prospectively collected database of FA patients, allows us the unique opportunity to analyze the natural history of this rare, clinically heterogeneous disorder in a large number of patients. Of the 754 subjects in this study, 601 (80%) experienced the onset of bone marrow failure (BMF), and 173 (23%) had a total of 199 neoplasms. Of these neoplasms, 120 (60%) were hematologic and 79 (40%) were nonhematologic. The risk of developing BMF and hematologic and nonhematologic neoplasms increased with advancing age with a 90%, 33%, and 28% cumulative incidence, respectively, by 40 years of age. Univariate analysis revealed a significantly earlier onset of BMF and poorer survival for complementation group C compared with groups A and G; however, there was no significant difference in the time to hematologic or nonhematologic neoplasm development between these groups. Multivariate analysis of overall survival time shows that FANCCmutations (P = .007) and hematopoietic stem cell transplantation (P = < .0001) define a poor-risk subgroup. The results of this study of patients registered in the IFAR over a 20-year period provide information that will enable better prediction of outcome and aid clinicians with decisions regarding major therapeutic modalities.

scholarly journals Fanconi Anemia Proteins FANCA, FANCC, and FANCG/XRCC9 Interact in a Functional Nuclear Complex

1999 ◽  
Vol 19 (7) ◽  
pp. 4866-4873 ◽  
Author(s):  
Irene Garcia-Higuera ◽  
Yanan Kuang ◽  
Dieter Näf ◽  
Jennifer Wasik ◽  
Alan D. D’Andrea
Keyword(s):  
Nuclear Localization ◽  
Fanconi Anemia ◽  
Autosomal Recessive ◽  
Nuclear Protein ◽  
Cancer Susceptibility ◽  
Clinical Phenotype ◽  
Normal Cells ◽  
Amino Terminal ◽  
Nuclear Complex ◽  
Complementation Groups

ABSTRACT Fanconi anemia (FA) is an autosomal recessive cancer susceptibility syndrome with at least eight complementation groups (A to H). Three FA genes, corresponding to complementation groups A, C, and G, have been cloned, but their cellular function remains unknown. We have previously demonstrated that the FANCA and FANCC proteins interact and form a nuclear complex in normal cells, suggesting that the proteins cooperate in a nuclear function. In this report, we demonstrate that the recently cloned FANCG/XRCC9 protein is required for binding of the FANCA and FANCC proteins. Moreover, the FANCG protein is a component of a nuclear protein complex containing FANCA and FANCC. The amino-terminal region of the FANCA protein is required for FANCG binding, FANCC binding, nuclear localization, and functional activity of the complex. Our results demonstrate that the three cloned FA proteins cooperate in a large multisubunit complex. Disruption of this complex results in the specific cellular and clinical phenotype common to most FA complementation groups.

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