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

Harvard University, Cambridge, Massachusetts, United States
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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    • "Inactivation of this pathway occurs in patients suffering from the rare recessive disorder FA and is caused by bi-allelic germline mutations in one of at least 15 FA genes [5] . In addition, FA pathwayinactivation occurs at low frequency in various cancer entities among the general (non-FA) population, indicating a selective advantage during carcinogenesis, either through an early malignant transformation-promoting step due to an increased mutation rate or through an increased cellular tolerance towards abnormal DNA replication [6]. For example, proximal FA pathway inactivation due to rare mutations in FANCC or FANCG has been reported in pancreatic cancer [7, 8] and epigenetic inactivation of FANCF was found in a large variety of different tumors, including bladder cancer [9], breast cancer [10], cervical cancer [11], head and neck cancer [12], lung cancer [12] and ovarian cancer [13]. "
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    ABSTRACT: Purpose: DNA repair defects due to detrimental BRCA2-mutations confer increased susceptibility towards DNA interstrand-crosslinking (ICL) agents and define patient subpopulations for individualized genotype-based cancer therapy. However, due to the side effects of these drugs, there is a need to identify additional agents, which could be used alone or in combination with ICL-agents. Therefore, we investigated whether BRCA2-mutations might also increase the sensitivity towards TRAIL-receptors (TRAIL-R)-targeting compounds. Experimental design: Two independent model systems were applied: a BRCA2 gene knockout and a BRCA2 gene complementation model. The effects of TRAIL-R-targeting compounds and ICL-agents on cell viability, apoptosis and cell cycle distribution were compared in BRCA2-proficient versus-deficient cancer cells in vitro. In addition, the effects of the TRAIL-R2-targeting antibody LBY135 were assessed in vivo using a murine tumor xenograft model. Results: BRCA2-deficient cancer cells displayed an increased sensitivity towards TRAIL-R-targeting agents. These effects exceeded and were mechanistically distinguishable from the well-established effects of ICL-agents. In vitro, ICL-agents expectedly induced an early cell cycle arrest followed by delayed apoptosis, whereas TRAIL-R-targeting compounds caused early apoptosis without prior cell cycle arrest. In vivo, treatment with LBY135 significantly reduced the tumor growth of BRCA2-deficient cancer cells in a xenograft model. Conclusions: BRCA2 mutations strongly increase the in vitro- and in vivo-sensitivity of cancer cells towards TRAIL-R-mediated apoptosis. This effect is mechanistically distinguishable from the well-established ICL-hypersensitivity of BRCA2-deficient cells. Our study thus defines a new genetic subpopulation of cancers susceptible towards TRAIL-R-targeting compounds, which could facilitate novel therapeutic approaches for patients with BRCA2-deficient tumors.
    Full-text · Article · Feb 2016 · Oncotarget
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    • "Due to the complexity of the FA protein complex, the pathogenesis of bone marrow failure has not yet been completely unravelled. It was recently demonstrated that in FA, even before the clinical onset of bone marrow failure, p53 is hyperactivated in HSC, leading to a p21 (CDKN1A)-dependent cell cycle arrest and HSC functional defects (Kennedy & D'Andrea, 2005; Ceccaldi et al, 2012). In addition, it has been demonstrated that bone marrow failure in FA is associated with increased p38 (MAPK14) signalling and subsequent production of pro-inflammatory cytokines, including tumour necrosis factor a (TNFa) (Dufour et al, 2003; Anur et al, 2012). "
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    ABSTRACT: The pathophysiological mechanisms underlying chronic neutropenia are extensive, varying from haematopoietic stem cell disorders resulting in defective neutrophil production, to accelerated apoptosis of neutrophil progenitors or circulating mature neutrophils. While the knowledge concerning genetic defects associated with congenital neutropenia or bone marrow failure is increasing rapidly, the functional role and consequences of these genetic alterations is often not well understood. In addition, there is a large group of diseases, including primary immunodeficiencies and metabolic diseases, in which chronic neutropenia is one of the symptoms, while there is no clear bone marrow pathology or haematopoietic stem cell dysfunction. Altogether, these disease entities illustrate the complexity of normal neutrophil development, the functional role of the (bone marrow) microenvironment and the increased propensity to undergo apoptosis, which is typical for neutrophils. The large variety of disorders associated with chronic neutropenia makes classification almost impossible and possibly not desirable, based on the clinical phenotypes. However, a better understanding of the regulation of normal myeloid differentiation and neutrophil development is of great importance in the diagnostic evaluation of unexplained chronic neutropenia. In this review we propose insights in the pathophysiology of chronic neutropenia in the context of the functional role of key players during normal neutrophil development, neutrophil release and neutrophil survival.
    Full-text · Article · Oct 2015 · British Journal of Haematology
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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.
    Preview · Article · Oct 2013 · PLoS ONE
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