Kee Y, D’Andrea ADExpanded roles of the Fanconi anemia pathway in preserving genomic stability. Genes Dev 24:1680-1694

Department of Radiation Oncology and Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Genes & development (Impact Factor: 10.8). 08/2010; 24(16):1680-94. DOI: 10.1101/gad.1955310
Source: PubMed


Studying rare human genetic diseases often leads to a better understanding of normal cellular functions. Fanconi anemia (FA), for example, has elucidated a novel DNA repair mechanism required for maintaining genomic stability and preventing cancer. The FA pathway, an essential tumor-suppressive pathway, is required for protecting the human genome from a specific type of DNA damage; namely, DNA interstrand cross-links (ICLs). In this review, we discuss the recent progress in the study of the FA pathway, such as the identification of new FANCM-binding partners and the identification of RAD51C and FAN1 (Fanconi-associated nuclease 1) as new FA pathway-related proteins. We also focus on the role of the FA pathway as a potential regulator of DNA repair choices in response to double-strand breaks, and its novel functions during the mitotic phase of the cell cycle.

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    • "Taken together, the in vivo and in vitro findings reveal that scMHF promotes specific Mph1 functions during replication-associated repair through its interaction with Mph1. Mph1 and its orthologs are indispensable for the cellular response to replication stress and DNA break repair, and mutations in FANCM can lead to a predisposition to oncogenesis (Kee and D'Andrea 2010; Whitby 2010). "
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    ABSTRACT: Budding yeast Mph1 helicase and its orthologs drive multiple DNA transactions. Elucidating the mechanisms that regulate these motor proteins is central to understanding genome maintenance processes. Here, we show that the conserved histone fold MHF complex promotes Mph1-mediated repair of damaged replication forks but does not influence the outcome of DNA double-strand break repair. Mechanistically, scMHF relieves the inhibition imposed by the structural maintenance of chromosome protein Smc5 on Mph1 activities relevant to replication-associated repair through binding to Mph1 but not DNA. Thus, scMHF is a function-specific enhancer of Mph1 that enables flexible response to different genome repair situations. © 2015 Xue et al.; Published by Cold Spring Harbor Laboratory Press.
    Full-text · Article · May 2015 · Genes & development
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    • "However, we cannot exclude the possibility of arsenic disrupting the FA/BRCA pathway through additional mechanism(s), as the route must coordinate with other DNA damage-responsive events to stabilize the stalled replication fork, to convey signals to DNA checkpoint pathways, and to facilitate recovery of replication forks after ICL lesions. Several proteins different from those of FA/BRCA such as ATR, -H2AX, or others involved in homologous recombination (HR) play part there (Kee and D'Andrea, 2010), and even those of the NER and BER pathways already known to be inhibited by arsenic (Kim and D'Andrea, 2012; Wilson and Seidman, 2010 ). Of interest here is the fact that cells defective in NER or HR, such as ataxia telangiectasia, xeroderma pigmentosum, or BRCA2-deficient cells are more susceptible to arsenite exposure (Mei et al., 2003; Shen et al., 2009; Ying et al., 2009). "
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    ABSTRACT: Chronic arsenic exposure is known to enhance the genotoxicity/carcinogenicity of other DNA-damaging agents by inhibiting DNA repair activities. Interference with nucleotide excision repair and base excision repair are well documented, but interactions with other DNA repair pathways are poorly explored so far. The Fanconi anemia FA/BRCA pathway is a DNA repair mechanism required for maintaining genomic stability and preventing cancer. Here, interactions between arsenic compounds and the FA/BRCA pathway were explored by using isogenic FANCD2−/− (FA/BRCA-deficient) and FANCD2+/+ (FA/BRCA-corrected) human fibroblasts. To study whether arsenic disrupts the normal FA/BRCA function, FANCD2+/+ cells were preexposed to subtoxic concentrations of the trivalent arsenic compounds methylarsonous acid (MMAIII) and arsenic trioxide (ATO) for 2 weeks. The cellular response to mitomicin-C, hydroxyurea, or diepoxybutane, typical inducers of the studied pathway, was then evaluated and compared to that of FANCD2−/− cells. Our results show that preexposure to the trivalent arsenicals MMAIII and ATO induces in corrected cells, a cellular FA/BRCA-deficient phenotype characterized by hypersensitivity, enhanced accumulation in the G2/M compartment and increased genomic instability—measured as micronuclei. Overall, our data demonstrate that environmentally relevant arsenic exposures disrupt the normal function of the FA/BRCA activity, supporting a novel source of arsenic co- and carcinogenic effects. This is the first study linking arsenic exposure with the FA/BRCA DNA repair pathway.
    Full-text · Article · Aug 2014 · Toxicological Sciences
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    • "At least 16 genes exist that are responsible for the known FA complementation groups (Table 2)7,8). All FA products function in a common DNA repair signaling pathway that closely cooperates with other DNA repair proteins for resolving interstrand cross-links during replication9). FA-A, B, C, E, F, G, L, and M associate in a nuclear core complex, which is required for FANCD2 activation via monoubiquitination during the S phase and in response to DNA damage10). "
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    ABSTRACT: Inherited bone marrow failure syndrome (IBMFS) encompasses a heterogeneous and complex group of genetic disorders characterized by physical malformations, insufficient blood cell production, and increased risk of malignancies. They often have substantial phenotype overlap, and therefore, genotyping is often a critical means of establishing a diagnosis. Current advances in the field of IBMFSs have identified multiple genes associated with IBMFSs and their pathways: genes involved in ribosome biogenesis, such as those associated with Diamond-Blackfan anemia and Shwachman-Diamond syndrome; genes involved in telomere maintenance, such as dyskeratosis congenita genes; genes encoding neutrophil elastase or neutrophil adhesion and mobility associated with severe congenital neutropenia; and genes involved in DNA recombination repair, such as those associated with Fanconi anemia. Early and adequate genetic diagnosis is required for proper management and follow-up in clinical practice. Recent advances using new molecular technologies, including next generation sequencing (NGS), have helped identify new candidate genes associated with the development of bone marrow failure. Targeted NGS using panels of large numbers of genes is rapidly gaining potential for use as a cost-effective diagnostic tool for the identification of mutations in newly diagnosed patients. In this review, we have described recent insights into IBMFS and how they are advancing our understanding of the disease's pathophysiology; we have also discussed the possible implications they will have in clinical practice for Korean patients.
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