Loss of the Fanconi anemia–associated protein NIPA causes bone marrow failure (original) (raw)
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The Fanconi Anemia/BRCA pathway: new faces in the crowd
Genes & Development, 2005
Over the past few years, study of the rare inherited chromosome instability disorder, Fanconi Anemia (FA), has uncovered a novel DNA damage response pathway. Through the cooperation of multiple proteins, this pathway regulates a complicated cellular response to DNA cross-linking agents and other genotoxic stresses. In this article we review recent data identifying new components of the FA pathway that implicate it in several aspects of the DNA damage response, including the direct processing of DNA, translesion synthesis, homologous recombination, and cell cycle regulation. We also discuss new findings that explain how the FA pathway is regulated through the processes of ubiquitination and deubiquitination. We then consider the clinical implications of our current understanding of the FA pathway, particularly in the development and treatment of malignancy in heterozygous carriers of FA mutations or in patients with sporadic cancers. We consider how recent studies of p53-mediated apoptosis and loss of p53 function in models of FA may help explain the clinical features of the disease and finally present a hypothesis to account for the specificity of the FA pathway in the response to DNA cross-links.
The Fanconi anemia pathway: repairing the link between DNA damage and squamous cell carcinoma
Mutation research
Fanconi anemia (FA) is a rare inherited recessive disease caused by mutations in one of fifteen genes known to encode FA pathway components. In response to DNA damage, nuclear FA proteins associate into high molecular weight complexes through a cascade of post-translational modifications and physical interactions, followed by the repair of damaged DNA. Hematopoietic cells are particularly sensitive to the loss of these interactions, and bone marrow failure occurs almost universally in FA patients. FA as a disease is further characterized by cancer susceptibility, which highlights the importance of the FA pathway in tumor suppression, and will be the focus of this review. Acute myeloid leukemia is the most common cancer type, often subsequent to bone marrow failure. However, FA patients are also at an extreme risk of squamous cell carcinoma (SCC) of the head and neck and gynecological tract, with an even greater incidence in those individuals who have received a bone marrow transplan...
Blood, 2010
Fanconi anemia (FA) is an inherited chromosomal instability syndrome characterized by bone marrow failure, myelodysplasia (MDS), and acute myeloid leukemia (AML). Eight FA proteins associate in a nuclear core complex to monoubiquitinate FANCD2/FANCI in response to DNA damage. Additional functions have been described for some of the core complex proteins; however, in vivo genetic proof has been lacking. Here we show that double-mutant Fancc−/−;Fancg−/− mice develop spontaneous hematologic sequelae including bone marrow failure, AML, MDS and complex random chromosomal abnormalities that the single-mutant mice do not. This genetic model provides evidence for unique core complex protein function independent of their ability to monoubiquitinate FANCD2/FANCI. Importantly, this model closely recapitulates the phenotypes found in FA patients and may be useful as a preclinical platform to evaluate the molecular pathogenesis of spontaneous bone marrow failure, MDS and AML in FA.
…, 1996
Hypersensitivity to cross-linking agents such as mitomycin C ("C) is characteristic of cells from patients suffering from the inherited bone marrow failure syndrome, Fanconi anemia (FA). Here, we link MMC hypersensitivity of Epstein-Barr virus (EBV)-immortalized FA lymphoblasts to a high susceptibility for apoptosis and p53 activation. In MMCtreated FA cells belonging to complementation group C (FA-C), apoptosis followed cell cycle arrest in the G2 phase. In stably transfected FA-C cells, plasmid-driven expression of the wild-type cytoplasmic FAC protein relieved MMC-dependent G2 arrest and suppressed p53 activation. However, in ANCON1 ANEMIA (FA) is an autosomal recessive disease characterized by developmental abnormalities (thumb and radius hypoplasia, microcephaly, growth delay, and kidney abnormalities), hyperpigmentation of the skin (cafk-au-lait spots), and life-threatening bone marrow failure.',' In addition, FA patients have a dramatically increased risk of developing malignancies, mainly acute myeloid leukemia and squamous cell carcinoma. Cultured FA cells exhibit an increased sensitivity to cross-linking agents such as mitomycin C ("C) and diepoxybutane.' Because of an increased level of spontaneous chromosomal aberrations in cultured cells, FA, like ataxia telangiectasia (AT) and Bloom syndrome (BS), is known as a chromosomal instability disorder. In FA, cell-fusion experiments have revealed four complementation groups, A to D'; recently, a fifth group was identified.4 In contrast to the UV-sensitivity diseases xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy, where disturbances in excision repair and transcription have been documented in detail,' the molecular bases of chromosomal instability disorders are still unknown. The FA group C gene, FAC (according to the nomenclature recommended by Lehmann et a16), cloned by Strathdee et al,7 is the first chromosomal instability disease gene isolated. The gene encodes a 63-kD polypeptide with no known sequence motifs that could provide a clue to its function. Since functionally active FAC protein apparently localizes to the cytoplasmic compartment of cells,8.' the protein is unlikely to be directly involved in DNA repair. Besides cross-linker hypersensitivity, cell cycle kinetic studies in primary fibroblasts and lymphocytes derived from FA patients revealed a characteristic spontaneous delay and arrest in G2."'.'' This phenomenon may explain the poor proliferative properties of primary FA cells. Since reduction F