The Fanconi Anemia/BRCA pathway: New faces in the crowd

Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Genes & Development (Impact Factor: 10.8). 01/2006; 19(24):2925-40. DOI: 10.1101/gad.1370505
Source: PubMed


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.

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Available from: Richard D Kennedy, Nov 07, 2015
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    • "Accumulation of monoubiquitinated FANCD2 on DNA lesions is visualized as nuclear foci using immune-staining with a FANCD2-specific antibody under a fluorescence microscope. The monoubiquitinated FANCD2 foci are used as markers for DNA ICL damage, which could be used for massive screening when combined with high-content screening tools [11,15]. In this study, we performed chemical library screening to find a small molecule inhibitor of the FA/BRCA pathway adopting a cell-based, high-content screening system using monoubiquitinated FANCD2 foci as markers for the activation of the FA/BRCA pathway. "
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    ABSTRACT: Modulation of the DNA repair pathway is an emerging target for the development of anticancer drugs. DNA interstrand cross-links (ICLs), one of the most severe forms of DNA damage caused by anticancer drugs such as cisplatin and mitomycin C (MMC), activates the Fanconi anemia (FA)/BRCA DNA repair pathway. Inhibition of the FA/BRCA pathway can enhance the cytotoxic effects of ICL-inducing anticancer drugs and can reduce anticancer drug resistance. To find FA/BRCA pathway inhibitory small molecules, we established a cell-based high-content screening method for quantitating the activation of the FA/BRCA pathway by measuring FANCD2 foci on DNA lesions and then applied our method to chemical screening. Using commercial LOPAC1280 chemical library screening, ouabain was identified as a competent FA/BRCA pathway inhibitory compound. Ouabain, a member of the cardiac glycoside family, binds to and inhibits Na(+)/K(+)-ATPase and has been used to treat heart disease for many years. We observed that ouabain, as well as other cardiac glycoside family members-digitoxin and digoxin-down-regulated FANCD2 and FANCI mRNA levels, reduced monoubiquitination of FANCD2, inhibited FANCD2 foci formation on DNA lesions, and abrogated cell cycle arrest induced by MMC treatment. These inhibitory activities of ouabain required p38 MAPK and were independent of cellular Ca(2+) ion increase or the drug uptake-inhibition effect of ouabain. Furthermore, we found that ouabain potentiated the cytotoxic effects of MMC in tumor cells. Taken together, we identified an additional effect of ouabain as a FA/BRCA pathway-inhibiting chemosensitization compound. The results of this study suggest that ouabain may serve as a chemosensitizer to ICL-inducing anticancer drugs.
    PLoS ONE 10/2013; 8(10):e75905. DOI:10.1371/journal.pone.0075905 · 3.23 Impact Factor
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    • "Fanconi anemia (FA) is a rare inherited disease, which is clinically associated with congenital malformations, bone marrow failure and increased susceptibility to the development of myeloid cancer and solid tumors [1]. The main cancer types observed are acute myeloid leukemia and squamous cell carcinomas of the head and neck, skin, gastrointestinal and genitourinary systems [2]. "
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    ABSTRACT: Fanconi anemia (FA) is a rare disease, autosomal recessive and X linked, which is clinically prone to development of hematological abnormalities and neoplasms, especially acute myeloid leukemia. In this work IL-10 and TGF-β levels were measured on FA patients' plasma since they are the regulatory cytokines of TNF-α and INF-γ which had been described to be overexpressed in this genetic disease. Our results show increased IL-10 plasma levels in 25% of FA patients studied, but levels of TGF-β within the normal range. TNF-α and INF-γ were also measured and found to be increased in 24% and 23% of FA patients, respectively. However, no inverse correlation was observed between augmented levels of IL-10 and TNF or IFN-γ. Patients with elevated levels of TNF-α and INF-γ presented bone marrow hypocellularity. IL-10 levels did not appear to be determinant for bone marrow cellularity. These data suggest that IL-10 is also a feature of Fanconi anemia pathophysiology.
    Cytokine 09/2013; 64(2). DOI:10.1016/j.cyto.2013.08.004 · 2.66 Impact Factor
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    • "The pathway was initially defined by virtue of its inactivation in a rare genetic disorder that bears the name, Fanconi Anemia. Subsequent characterization of the FA genes uncovered a critical DNA damage response pathway that is activated by DNA damage-stalled replication forks [1]. Activation of the FA pathway involves a complex signal transduction cascade with the mono-ubiquitination of the FANCD2/FANCI heterodimer as a key intermediary step [2] [3]. "
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    ABSTRACT: The Fanconi Anemia (FA) pathway encodes a DNA damage response activated by DNA damage-stalled replication forks. Current evidence suggests that the FA pathway initiates with DNA damage recognition by the FANCM complex (FANCM/FAAP24/MHF). However, genetic inactivation of FANCM in mouse and DT40 cells causes only a partial defect in the FA pathway activation, suggesting the existence of redundant DNA damage sensors. Here we show that the MutS homologs function in this capacity. A RNAi screen revealed that MSH2 silencing caused defective FA pathway activation, as assessed by damage-induced FANCD2 mono-ubiquitination. A similar FA pathway defect was observed with MSH3 or MSH6 silencing. MSH2 depletion caused cellular phenotypes associated with defective FA pathway, including mitomycin C hypersensitivity and chromosomal instability. Further, silencing of FANCM in MSH2 deficient HEC59 cells caused a more severe FA defect relative to comparable silencing in MSH2 complemented HEC59+Chr2 cells, suggesting redundant functions between MSH2 and FANCM. Consistent with this hypothesis, depletion of MSH2 resulted in defective chromatin localization of the FA core complex upon DNA damage. Further, MSH2 was co-purified and co-immunoprecipitated with FA core complex components. Taken together, our results suggest that human MutS homologs and FANCM complexes function as redundant DNA damage sensors of the FA pathway.
    DNA repair 12/2011; 10(12):1203-12. DOI:10.1016/j.dnarep.2011.09.006 · 3.11 Impact Factor
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