Expression cloning of a cDNA for the major Fanconi anemia gene, FAA
ABSTRACT Fanconi anaemia (FA) is an autosomal recessive disorder characterized by a diversity of clinical symptoms including skeletal abnormalities, progressive bone marrow failure and a marked predisposition to cancer. FA cells exhibit chromosomal instability and hyper-responsiveness to the clastogenic and cytotoxic effects of bifunctional alkylating (cross-linking) agents, such as diepoxybutane (DEB) and mitomycin C (MMC). Five complementation groups (A-E) have been distinguished on the basis of somatic cell hybridization experiments, with group FA-A accounting for over 65% of the cases analysed. A cDNA for the group C gene (FAC) was reported and localized to chromosome 9q22.3 (ref.8). Genetic map positions were recently reported for two more FA genes, FAA (16q24.3) and FAD (3p22-26). Here we report the isolation of a cDNA representing the FAA gene, following an expression cloning method similar to the one used to clone the FAC gene. The 5.5-kb cDNA has an open reading frame of 4,368 nucleotides. In contrast to the 63-kD cytosolic protein encoded by the FAC gene, the predicted FAA protein (M(r) 162, 752) contains two overlapping bipartite nuclear localization signals and a partial leucine zipper consensus, which are suggestive of a nuclear localization.
Full-textDOI: · Available from: David F Callen, Mar 21, 2014
- SourceAvailable from: Madeleine Carreau
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- "FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ/BRIP1/ BACH1, FANCL/PHF9, FANCM/HEF, FANCN/PALB2, and FANCP/SLX4                  "
ABSTRACT: In recent years, Fanconi anemia (FA) has been the subject of intense investigations, primarily in the DNA repair research field. Many discoveries have led to the notion of a canonical pathway, termed the FA pathway, where all FA proteins function sequentially in different protein complexes to repair DNA cross-link damages. Although a detailed architecture of this DNA cross-link repair pathway is emerging, the question of how a defective DNA cross-link repair process translates into the disease phenotype is unresolved. Other areas of research including oxidative metabolism, cell cycle progression, apoptosis, and transcriptional regulation have been studied in the context of FA, and some of these areas were investigated before the fervent enthusiasm in the DNA repair field. These other molecular mechanisms may also play an important role in the pathogenesis of this disease. In addition, several FA-interacting proteins have been identified with roles in these "other" nonrepair molecular functions. Thus, the goal of this paper is to revisit old ideas and to discuss protein-protein interactions related to other FA-related molecular functions to try to give the reader a wider perspective of the FA molecular puzzle.Anemia 03/2012; 2012:425814. DOI:10.1155/2012/425814
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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- "FANCA, FANCB, FANCC, FANCD1(BRCA2), FANCD2, FANCE, FANCF, FANCG(XRCC9), FANCI, FANCJ(BRIP1), FANCL, FANCM, FANCN(PALB2)), FANCO (RAD51C), and FANCP(SLX4) (de Winter et al., 1998, 2000a, 2000b; Dorsman et al., 2007; Gurtan et al., 2006; Howlett et al., 2002; Kim et al., 2010; Levitus et al., 2005; Levran et al., 2005; Lo Ten Foe et al., 1996; Meetei et al., 2003, 2004a, 2004b, 2005; Reid et al., 2007; Sims et al., 2007; Smogorzewska et al., 2007; Strathdee et al., 1992; Timmers et al., 2001; Vaz et al., 2010; Wang, 2007; Xia et al., 2007 "
ABSTRACT: Fanconi anemia (FA) is a human disease of bone marrow failure, leukemia, squamous cell carcinoma, and developmental anomalies, including hypogonadism and infertility. Bone marrow transplants improve hematopoietic phenotypes but do not prevent other cancers. FA arises from mutation in any of the 15 FANC genes that cooperate to repair double stranded DNA breaks by homologous recombination. Zebrafish has a single ortholog of each human FANC gene and unexpectedly, mutations in at least two of them (fancl and fancd1(brca2)) lead to female-to-male sex reversal. Investigations show that, as in human, zebrafish fanc genes are required for genome stability and for suppressing apoptosis in tissue culture cells, in embryos treated with DNA damaging agents, and in meiotic germ cells. The sex reversal phenotype requires the action of Tp53 (p53), an activator of apoptosis. These results suggest that in normal sex determination, zebrafish oocytes passing through meiosis signal the gonadal soma to maintain expression of aromatase, an enzyme that converts androgen to estrogen, thereby feminizing the gonad and the individual. According to this model, normal male and female zebrafish differ in genetic factors that control the strength of the late meiotic oocyte-derived signal, probably by regulating the number of meiotic oocytes, which environmental factors can also alter. Transcripts from fancd1(brca2) localize at the animal pole of the zebrafish oocyte cytoplasm and are required for normal oocyte nuclear architecture, for normal embryonic development, and for preventing ovarian tumors. Embryonic DNA repair and sex reversal phenotypes provide assays for the screening of small molecule libraries for therapeutic substances for FA.Methods in cell biology 01/2011; 105:461-90. DOI:10.1016/B978-0-12-381320-6.00020-5 · 1.42 Impact Factor