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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: 12.64). 08/2010; 24(16):1680-94. DOI: 10.1101/gad.1955310
Source: PubMed

ABSTRACT 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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    • "FANCD2-FANCI then recruits further downstream factors and interacts with HR and TLS proteins, finally facilitating HR-dependent ICL repair [9]. It is also proposed that a parallel crosstalk with S-phase checkpoint proteins mediates and coordinates ICL repair with other DNA damage response mechanisms [9]. Recent work in higher eukaryotes identified and characterized FAN1 (Fanconi anemia-associated nuclease 1, or FANCD2/FANCI- associated nuclease 1) [13] [14] [15] [16] [17] [18]. "
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    ABSTRACT: DNA interstrand cross-links (ICLs) represent a physical barrier to the progression of cellular machinery involved in DNA metabolism. Thus, this type of adduct represents a serious threat to genomic stability and as such, several DNA repair pathways have evolved in both higher and lower eukaryotes to identify this type of damage and restore the integrity of the genetic material. Human cells possess a specialized ICL-repair system, the Fanconi anemia (FA) pathway. Conversely yeasts rely on the concerted action of several DNA repair systems. Recent work in higher eukaryotes identified and characterized a novel conserved FA component, FAN1 (Fanconi anemia-associated nuclease 1, or FANCD2/FANCI-associated nuclease 1). In this study, we characterize Fan1 in the yeast Schizosaccharomyces pombe. Using standard genetics, we demonstrate that Fan1 is a key component of a previously unidentified ICL-resolution pathway. Using high-throughput synthetic genetic arrays, we also demonstrate the existence of a third pathway of ICL repair, dependent on the SUMO E3 ligase Pli1. Finally, using sequence-threaded homology models, we predict and validate key residues essential for Fan1 activity in ICL repair.
    DNA repair 11/2013; 24(12). DOI:10.1016/j.dnarep.2013.10.003 · 3.36 Impact Factor
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    • "Fanconi anemia (FA) is a rare multigenetic syndrome characterized by developmental defects, bone marrow failure and cancer predisposition [1] [2] [3]. Any defect in the 15 known FANC genes will induce failure of DNA damage repair, leading to FA [2] [3] [4] [5] [6] [7]. FA cells are highly sensitive to agents that can cause DNA interstrand crosslinks (ICLs), which are abnormal structures blocking DNA replication . "
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    ABSTRACT: MHF1 and MHF2 are histone-fold-containing FANCM-associated proteins. FANCM is a Fanconi anemia complementation group protein. We previously obtained high-resolution structures of MHF1-MHF2 (MHF) and MHF in complex with a fragment of FANCM (MHF-FANCM-F). Here, we use small angle X-ray scattering (SAXS) to investigate the solution behaviors of these protein complexes. In combination with crystallographic data, the results of the SAXS study reveal that a long, positively charged patch exposed on the surface of the MHF complex plays a critical role in double-stranded DNA (dsDNA) binding. MHF2, MHF1 and FANCM-Fphysically interact by molecular sieving(View interaction)MHF1 and MHF2bind by x ray scattering (View interaction) MHF1 and MHF2bind by molecular sieving (View interaction) MHF1, FANCM-F and MHF2physically interact by x ray scattering (View interaction).
    FEBS letters 07/2013; 587(18). DOI:10.1016/j.febslet.2013.07.022 · 3.34 Impact Factor
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    • "FANCE, FANCF, FANCG, FANCL, and FANCM functions as an E3 ubiquitin ligase and mediates the activation of the ID complex, which is a heterodimer composed of FANCD2 and FANCI. Once monoubiquitinated, it interacts with classical tumor suppressors downstream of the FA pathway including FANCD1/BRCA2, FANCN/PALB2, FANCJ/BRIP1, and FAN CO/Rad51C and thereby contributes to DNA repair via homologous recombination (HR) [9]. Defects in any of the gene products associated with the FA pathway result in similar cellular abnormalities. "
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    ABSTRACT: Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome. FA patients suffer to varying degrees from a heterogeneous range of developmental defects and, in addition, have an increased likelihood of developing cancer. Almost all FA patients develop a severe, progressive bone marrow failure syndrome, which impacts upon the production of all hematopoietic lineages and, hence, is thought to be driven by a defect at the level of the hematopoietic stem cell (HSC). This hypothesis would also correlate with the very high incidence of MDS and AML that is observed in FA patients. In this paper, we discuss the evidence that supports the role of dysfunctional HSC biology in driving the etiology of the disease. Furthermore, we consider the different model systems currently available to study the biology of cells defective in the FA signaling pathway and how they are informative in terms of identifying the physiologic mediators of HSC depletion and dissecting their putative mechanism of action. Finally, we ask whether the insights gained using such disease models can be translated into potential novel therapeutic strategies for the treatment of the hematologic disorders in FA patients.
    Anemia 05/2012; 2012(1):265790. DOI:10.1155/2012/265790
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