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Alan D Dandrea - One of the best experts on this subject based on the ideXlab platform.
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the Fanconi Anemia pathway in cancer
Annual Review of Cancer Biology, 2019Co-Authors: Joshi Niraj, Anniina Farkkila, Alan D DandreaAbstract:Fanconi Anemia (FA) is a complex genetic disorder characterized by bone marrow failure (BMF), congenital defects, inability to repair DNA interstrand cross-links (ICLs), and cancer predisposition. FA presents two seemingly opposite characteristics: (a) massive cell death of the hematopoietic stem and progenitor cell (HSPC) compartment due to extensive genomic instability, leading to BMF, and (b) uncontrolled cell proliferation leading to FA-associated malignancies. The canonical function of the FA proteins is to collaborate with several other DNA repair proteins to eliminate clastogenic (chromosome-breaking) effects of DNA ICLs. Recent discoveries reveal that the FA pathway functions in a critical tumor-suppressor network to preserve genomic integrity by stabilizing replication forks, mitigating replication stress, and regulating cytokinesis. Homozygous germline mutations (biallelic) in 22 FANC genes cause FA, whereas heterozygous germline mutations in some of the FANC genes (monoallelic), such as BRCA1 and BRCA2, do not cause FA but significantly increase cancer susceptibility sporadically in the general population. In this review, we discuss our current understanding of the functions of the FA pathway in the maintenance of genomic stability, and we present an overview of the prevalence and clinical relevance of somatic mutations in FA genes.
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Fanconi Anemia pathway
Current Biology, 2017Co-Authors: Alfredo E Rodriguez, Alan D DandreaAbstract:Rodriguez and D'Andrea introduce the Fanconi Anemia pathway and its role in DNA repair and other cellular functions.
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molecular pathogenesis and clinical management of Fanconi Anemia
Journal of Clinical Investigation, 2012Co-Authors: Younghoon Kee, Alan D DandreaAbstract:Fanconi Anemia (FA) is a rare genetic disorder associated with a high frequency of hematological abnormalities and congenital anomalies. Based on multilateral efforts from basic scientists and clinicians, significant advances in our knowledge of FA have been made in recent years. Here we review the clinical features, the diagnostic criteria, and the current and future therapies of FA and describe the current understanding of the molecular basis of the disease.
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regulation of rev1 by the Fanconi Anemia core complex
Nature Structural & Molecular Biology, 2012Co-Authors: Kailin Yang, Donniphat Dejsuphong, Alan D DandreaAbstract:The Fanconi Anemia pathway is involved in the repair of DNA interstrand cross-links, but it is also involved in regulation of translesion synthesis (TLS). The protein FAAP20 is now identified as a subunit of the Fanconi Anemia core complex. FAAP20 interacts with TLS DNA polymerase Rev1, stabilizing Rev1's association with PCNA and promoting DNA damage bypass.
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xpf ercc1 participates in the Fanconi Anemia pathway of cross link repair
Molecular and Cellular Biology, 2009Co-Authors: Nikhil R Bhagwat, Alan D Dandrea, Laura J Niedernhofer, Anderson T Wang, Anna L Olsen, Katsuhiro Hanada, Patricia Stuckert, Roland Kanaar, Peter J MchughAbstract:Interstrand cross-links (ICLs) prevent DNA strand separation and, therefore, transcription and replication, making them extremely cytotoxic. The precise mechanism by which ICLs are removed from mammalian genomes largely remains elusive. Genetic evidence implicates ATR, the Fanconi Anemia proteins, proteins required for homologous recombination, translesion synthesis, and at least two endonucleases, MUS81-EME1 and XPF-ERCC1. ICLs cause replication-dependent DNA double-strand breaks (DSBs), and MUS81-EME1 facilitates DSB formation. The subsequent repair of these DSBs occurs via homologous recombination after the ICL is unhooked by XPF-ERCC1. Here, we examined the effect of the loss of either nuclease on FANCD2 monoubiquitination to determine if the nucleolytic processing of ICLs is required for the activation of the Fanconi Anemia pathway. FANCD2 was monoubiquitinated in Mus81(-/-), Ercc1(-/-), and XPF-deficient human, mouse, and hamster cells exposed to cross-linking agents. However, the monoubiquitinated form of FANCD2 persisted longer in XPF-ERCC1-deficient cells than in wild-type cells. Moreover, the levels of chromatin-bound FANCD2 were dramatically reduced and the number of ICL-induced FANCD2 foci significantly lower in XPF-ERCC1-deficient cells. These data demonstrate that the unhooking of an ICL by XPF-ERCC1 is necessary for the stable localization of FANCD2 to the chromatin and subsequent homologous recombination-mediated DSB repair.
Agata Smogorzewska - One of the best experts on this subject based on the ideXlab platform.
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natural history and management of Fanconi Anemia patients with head and neck cancer a 10 year follow up
Laryngoscope, 2016Co-Authors: David I Kutler, Francis P Lach, Arleen D Auerbach, Krupa R Patel, Jennifer A Kennedy, Erica Sanborn, Marc Cohen, William I Kuhel, Agata SmogorzewskaAbstract:Objectives/Hypothesis To describe the management and outcomes of Fanconi Anemia (FA) patients with head and neck squamous cell carcinoma. Study Design Cohort study. Methods Demographic information, prognostic factors, therapeutic management, and survival outcomes for FA patients enrolled in the International Fanconi Anemia Registry who developed head and neck squamous cell carcinoma (HNSCC) were analyzed. Results Thirty-five FA patients were diagnosed with HNSCC at a mean age of 32 years. The most common site of primary cancer was the oral cavity (26 of 35, 74%). Thirty patients underwent surgical resection of the cancer. Sixteen patients received radiation therapy with an average radiation dose of 5,050 cGy. The most common toxicities were high-grade mucositis (9 of 16, 56%), hematologic abnormalities (8 of 16, 50%), and dysphagia (8 of 16, 50%). Three patients received conventional chemotherapy and had significant complications, whereas three patients who received targeted chemotherapy with cetuximab had fewer toxicities. The 5-year overall survival rate was 39%, with a cause-specific survival rate of 47%. Conclusions Fanconi Anemia patients have a high risk of developing aggressive HNSCC at an early age. Fanconi Anemia patients can tolerate complex ablative and reconstructive surgeries, but careful postoperative care is required to reduce morbidity. The treatment of FA-associated HNSCC is difficult secondary to the poor tolerance of radiation and chemotherapy. However, radiation should be used for high-risk cancers due to the poor survival in these patients. Level of Evidence 4. Laryngoscope, 2015
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snapshot Fanconi Anemia and associated proteins
Cell, 2015Co-Authors: Anderson T Wang, Agata SmogorzewskaAbstract:Fanconi Anemia is a genetic disorder resulting from biallelic mutations in one of the 17 FANC genes. It is characterized by congenital abnormalities, bone marrow failure, and cancer predisposition. The underlying cause is genomic instability resulting from the deficiency in replication-dependent DNA interstrand crosslink repair pathway commonly referred to as the Fanconi Anemia-BRCA pathway. This SnapShot presents the key factors involved.
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regulation of multiple dna repair pathways by the Fanconi Anemia protein slx4
Blood, 2013Co-Authors: Yonghwan Kim, Francis P Lach, Arleen D Auerbach, Gabriella S Spitz, Uma Veturi, Agata SmogorzewskaAbstract:SLX4, the newly identified Fanconi Anemia protein, FANCP, is implicated in repairing DNA damage induced by DNA interstrand cross-linking (ICL) agents, topoisomerase I (TOP1) inhibitors, and in Holliday junction resolution. It interacts with and enhances the activity of XPF-ERCC1, MUS81-EME1, and SLX1 nucleases, but the requirement for the specific nucleases in SLX4 function is unclear. Here, by complementing a null FA-P Fanconi Anemia cell line with SLX4 mutants that specifically lack the interaction with each of the nucleases, we show that the SLX4-dependent XPF-ERCC1 activity is essential for ICL repair but is dispensable for repairing TOP1 inhibitor-induced DNA lesions. Conversely, MUS81-SLX4 interaction is critical for resistance to TOP1 inhibitors but is less important for ICL repair. Mutation of SLX4 that abrogates interaction with SLX1 results in partial resistance to both cross-linking agents and TOP1 inhibitors. These results demonstrate that SLX4 modulates multiple DNA repair pathways by regulating appropriate nucleases.
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structure of the fanci fancd2 complex insights into the Fanconi Anemia dna repair pathway
Science, 2011Co-Authors: Guozhou Xu, Agata Smogorzewska, Stephen J Elledge, Nicole S Persky, Derek G Rudge, Olga Buzovetsky, Nikola P PavletichAbstract:Fanconi Anemia is a cancer predisposition syndrome caused by defects in the repair of DNA interstrand cross-links (ICLs). Central to this pathway is the Fanconi Anemia I–Fanconi Anemia D2 (FANCI-FANCD2) (ID) complex, which is activated by DNA damage–induced phosphorylation and monoubiquitination. The 3.4 angstrom crystal structure of the ~300 kilodalton ID complex reveals that monoubiquitination and regulatory phosphorylation sites map to the I-D interface, suggesting that they occur on monomeric proteins or an opened-up complex and that they may serve to stabilize I-D heterodimerization. The 7.8 angstrom electron-density map of FANCI-DNA crystals and in vitro data show that each protein has binding sites for both single- and double-stranded DNA, suggesting that the ID complex recognizes DNA structures that result from the encounter of replication forks with an ICL.
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mutations of the slx4 gene in Fanconi Anemia
Nature Genetics, 2011Co-Authors: Yonghwan Kim, Helmut Hanenberg, Francis P Lach, Arleen D Auerbach, Rohini Desetty, Agata SmogorzewskaAbstract:Agata Smogorzewska and colleagues report mutations in SLX4 in a new subtype of Fanconi Anemia. SLX4 is an endonuclease involved in DNA maintenance and repair.
Ashley J. Deans - One of the best experts on this subject based on the ideXlab platform.
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mechanism of ubiquitination and deubiquitination in the Fanconi Anemia pathway
Molecular Cell, 2017Co-Authors: Sylvie Van Twest, Vincent J Murphy, Charlotte Hodson, Paolo Swuec, Julienne J Orourke, Wayne Crismani, Jörg Heierhorst, Ashley J. DeansAbstract:Summary Monoubiquitination and deubiquitination of FANCD2:FANCI heterodimer is central to DNA repair in a pathway that is defective in the cancer predisposition syndrome Fanconi Anemia (FA). The "FA core complex" contains the RING-E3 ligase FANCL and seven other essential proteins that are mutated in various FA subtypes. Here, we purified recombinant FA core complex to reveal the function of these other proteins. The complex contains two spatially separate FANCL molecules that are dimerized by FANCB and FAAP100. FANCC and FANCE act as substrate receptors and restrict monoubiquitination to the FANCD2:FANCI heterodimer in only a DNA-bound form. FANCA and FANCG are dispensable for maximal in vitro ubiquitination. Finally, we show that the reversal of this reaction by the USP1:UAF1 deubiquitinase only occurs when DNA is disengaged. Our work reveals the mechanistic basis for temporal and spatial control of FANCD2:FANCI monoubiquitination that is critical for chemotherapy responses and prevention of Fanconi Anemia.
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the Fanconi Anemia dna repair pathway structural and functional insights into a complex disorder
Annual Review of Biophysics, 2014Co-Authors: Helen Walden, Ashley J. DeansAbstract:Mutations in any of at least sixteen FANC genes (FANCA–Q) cause Fanconi Anemia, a disorder characterized by sensitivity to DNA interstrand crosslinking agents. The clinical features of cytopenia, developmental defects, and tumor predisposition are similar in each group, suggesting that the gene products participate in a common pathway. The Fanconi Anemia DNA repair pathway consists of an anchor complex that recognizes damage caused by interstrand crosslinks, a multisubunit ubiquitin ligase that monoubiquitinates two substrates, and several downstream repair proteins including nucleases and homologous recombination enzymes. We review progress in the use of structural and biochemical approaches to understanding how each FANC protein functions in this pathway.
Helmut Hanenberg - One of the best experts on this subject based on the ideXlab platform.
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acquisition of relative interstrand crosslinker resistance and parp inhibitor sensitivity in Fanconi Anemia head and neck cancers
Clinical Cancer Research, 2015Co-Authors: Anne J Lombardi, Helmut Hanenberg, Elizabeth E Hoskins, Grant D Foglesong, Kathryn A Wikenheiserbrokamp, Lisa Wiesmuller, Paul R Andreassen, Allison J JacobsAbstract:Purpose: Fanconi Anemia is an inherited disorder associated with a constitutional defect in the Fanconi Anemia DNA repair machinery that is essential for resolution of DNA interstrand crosslinks. Individuals with Fanconi Anemia are predisposed to formation of head and neck squamous cell carcinomas (HNSCC) at a young age. Prognosis is poor, partly due to patient intolerance of chemotherapy and radiation requiring dose reduction, which may lead to early recurrence of disease. Experimental Design: Using HNSCC cell lines derived from the tumors of patients with Fanconi Anemia, and murine HNSCC cell lines derived from the tumors of wild-type and Fancc −/− mice, we sought to define Fanconi Anemia–dependent chemosensitivity and DNA repair characteristics. We utilized DNA repair reporter assays to explore the preference of Fanconi Anemia HNSCC cells for non-homologous end joining (NHEJ). Results: Surprisingly, interstrand crosslinker (ICL) sensitivity was not necessarily Fanconi Anemia–dependent in human or murine cell systems. Our results suggest that the increased Ku-dependent NHEJ that is expected in Fanconi Anemia cells did not mediate relative ICL resistance. ICL exposure resulted in increased DNA damage sensing and repair by PARP in Fanconi Anemia–deficient cells. Moreover, human and murine Fanconi Anemia HNSCC cells were sensitive to PARP inhibition, and sensitivity of human cells was attenuated by Fanconi Anemia gene complementation. Conclusions: The observed reliance upon PARP-mediated mechanisms reveals a means by which Fanconi Anemia HNSCCs can acquire relative resistance to the ICL-based chemotherapy that is a foundation of HNSCC treatment, as well as a potential target for overcoming chemoresistance in the chemosensitive individual. Clin Cancer Res; 21(8); 1962–72. ©2015 AACR .
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mutations of the slx4 gene in Fanconi Anemia
Nature Genetics, 2011Co-Authors: Yonghwan Kim, Helmut Hanenberg, Francis P Lach, Arleen D Auerbach, Rohini Desetty, Agata SmogorzewskaAbstract:Agata Smogorzewska and colleagues report mutations in SLX4 in a new subtype of Fanconi Anemia. SLX4 is an endonuclease involved in DNA maintenance and repair.
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mutation of the rad51c gene in a Fanconi Anemia like disorder
Nature Genetics, 2010Co-Authors: Helmut Hanenberg, Beatrice Schuster, Verena Erven, Kornelia Neveling, Daniela Endt, Ian Kesterton, Constanze Wiek, Karen Barker, Flavia AutoreAbstract:Christopher Mathew and colleagues report a homozygous germline mutation of RAD51C in a Fanconi Anemia-like disorder. Mutation of RAD51C, encoding a protein involved in homologous recombination-mediated DNA repair, leads to hypersensitivity to DNA cross-linking agents.
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mutation of the rad51c gene in a Fanconi Anemia like disorder
Nature Genetics, 2010Co-Authors: Fiona Vaz, Helmut Hanenberg, Beatrice Schuster, Verena Erven, Kornelia Neveling, Daniela Endt, Constanze Wiek, Karen Barker, Ian KestertonAbstract:Fanconi Anemia (FA) is a rare chromosomal-instability disorder associated with a variety of developmental abnormalities, bone marrow failure and predisposition to leukemia and other cancers. We have identified a homozygous missense mutation in the RAD51C gene in a consanguineous family with multiple severe congenital abnormalities characteristic of FA. RAD51C is a member of the RAD51-like gene family involved in homologous recombination-mediated DNA repair. The mutation results in loss of RAD51 focus formation in response to DNA damage and in increased cellular sensitivity to the DNA interstrand cross-linking agent mitomycin C and the topoisomerase-1 inhibitor camptothecin. Thus, biallelic germline mutations in a RAD51 paralog are associated with an FA-like syndrome.
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fanci is a second monoubiquitinated member of the Fanconi Anemia pathway
Nature Structural & Molecular Biology, 2007Co-Authors: Ashley E Sims, Kornelia Neveling, Francis P Lach, Elizabeth Spiteri, Robert J Sims, Adriana Arita, Thomas Landers, Melanie Wurm, Marcel Freund, Helmut HanenbergAbstract:Activation of the Fanconi Anemia (FA) DNA damage–response pathway results in the monoubiquitination of FANCD2, which is regulated by the nuclear FA core ubiquitin ligase complex. A FANCD2 protein sequence–based homology search facilitated the discovery of FANCI, a second monoubiquitinated component of the FA pathway. Biallelic mutations in the gene coding for this protein were found in cells from four FA patients, including an FA-I reference cell line.
Ketan J Patel - One of the best experts on this subject based on the ideXlab platform.
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why does the bone marrow fail in Fanconi Anemia
Blood, 2014Co-Authors: Juan I Garaycoechea, Ketan J PatelAbstract:The inherited bone marrow failure (BMF) syndromes are a rare and diverse group of genetic disorders that ultimately result in the loss of blood production. The molecular defects underlying many of these conditions have been elucidated, and great progress has been made toward understanding the normal function of these gene products. This review will focus on perhaps the most well-known and genetically heterogeneous BMF syndrome: Fanconi Anemia. More specifically, this account will review the current state of our knowledge on why the bone marrow fails in this illness and what this might tell us about the maintenance of bone marrow function and hematopoiesis.
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formaldehyde catabolism is essential in cells deficient for the Fanconi Anemia dna repair pathway
Nature Structural & Molecular Biology, 2011Co-Authors: Iván V. Rosado, Minoru Takata, Gerry P. Crossan, Frederic Langevin, Ketan J PatelAbstract:Metabolism is predicted to generate formaldehyde, a toxic, simple, reactive aldehyde that can damage DNA. Here we report a synthetic lethal interaction in avian cells between ADH5, encoding the main formaldehyde-detoxifying enzyme, and the Fanconi Anemia (FA) DNA-repair pathway. These results define a fundamental role for the combined action of formaldehyde catabolism and DNA cross-link repair in vertebrate cell survival.
