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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    • "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.
    Korean Journal of Pediatrics 08/2014; 57(8):337-44. DOI:10.3345/kjp.2014.57.8.337
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    • "It is a genetically heterogeneous disease, with 16 complementation groups identified to date (19,21,22). Our current understanding is that the products of these genes coordinately function to promote genome stability with a specialized role in the repair of DNA inter-strand crosslinks (ICLs; 20,23,24) and certain endogenous lesions (25). Activation of the FA pathway is typically observed by mono-ubiquitination of the FANCD2 and FANCI proteins by the FA core complex (composed of at least eight FA proteins), promoting their recruitment to chromatin and focus formation (26–29). "
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    ABSTRACT: Accumulating evidence suggests that dormant DNA replication origins play an important role in the recovery of stalled forks. However, their functional interactions with other fork recovery mechanisms have not been tested. We previously reported intrinsic activation of the Fanconi anemia (FA) pathway in a tumor-prone mouse model (Mcm4chaos3) with a 60% loss of dormant origins. To understand this further, we introduced a null allele of Fancc (Fancc−), encoding a member of the FA core complex, into the Mcm4chaos3 background. Primary embryonic fibroblasts double homozygous for Mcm4chaos3 and Fancc− (Mcm4chaos3/chaos3;Fancc−/−) showed significantly increased levels of markers of stalled/collapsed forks compared to either single homozygote. Interestingly, a loss of dormant origins also increased the number of sites in which replication was delayed until prophase, regardless of FA pathway activation. These replication defects coincided with substantially elevated levels of genome instability in Mcm4chaos3/chaos3;Fancc−/− cells, resulting in a high rate of perinatal lethality of Mcm4chaos3/chaos3;Fancc−/− mice and the accelerated tumorigenesis of surviving mice. Together, these findings uncover a specialized role of dormant origins in replication completion while also identifying important functional overlaps between dormant origins and the FA pathway in maintaining fork progression, genome stability, normal development and tumor suppression.
    Nucleic Acids Research 03/2014; 42(9). DOI:10.1093/nar/gku170 · 9.11 Impact Factor
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    • "Figure 5D shows the binding of HOXC9 to the promoter of FANCM and to both the promoter and 3’ region of FEN1. FANCM is a component of the FANCM–FAAP24–MHF protein complex that binds to DNA with interstrand cross-links and is responsible for recruiting the FA core complex to the damaged site [38]. FEN1 (flap endonuclease 1) is essential for DNA replication and repair by removing RNA and DNA 5' flaps [39]. "
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    ABSTRACT: Cellular differentiation is characterized by the acquisition of specialized structures and functions, cell cycle exit, and global attenuation of the DNA damage response. It is largely unknown how these diverse cellular events are coordinated at the molecular level during differentiation. We addressed this question in a model system of neuroblastoma cell differentiation induced by HOXC9. We conducted a genome-wide analysis of the HOXC9-induced neuronal differentiation program. Microarray gene expression profiling revealed that HOXC9-induced differentiation was associated with transcriptional regulation of 2,370 genes, characterized by global upregulation of neuronal genes and downregulation of cell cycle and DNA repair genes. Remarkably, genome-wide mapping by ChIP-seq demonstrated that HOXC9 bound to 40% of these genes, including a large number of genes involved in neuronal differentiation, cell cycle progression and the DNA damage response. Moreover, we showed that HOXC9 interacted with the transcriptional repressor E2F6 and recruited it to the promoters of cell cycle genes for repressing their expression. Our results demonstrate that HOXC9 coordinates diverse cellular processes associated with differentiation by directly activating and repressing the transcription of distinct sets of genes.
    BMC Genomics 11/2013; 14(1):830. DOI:10.1186/1471-2164-14-830 · 3.99 Impact Factor
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