The Fanconi Anemia/BRCA Signaling Pathway: Disruption in Cisplatin-Sensitive Ovarian Cancers

D’Andrea, Alan D.

doi:10.4161/cc.2.4.413

Cited by 45 publications

(28 citation statements)

References 9 publications

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Section: Brca1-b Complex Is Required For Replication Stress Induced Cmentioning

confidence: 99%

“…Fanconi anemia (FA) is a rare genetic disorder associated with various developmental defects and a high incidence of malignancies [84][85][86]. The FA patients' cells are extremely sensitive to agents that induce DNA interstrand crosslinks [84][85][86] indicating that Bach1 plays a role in the DNA interstrand crosslink repair.In vitro studies suggest that Bach1 is a DNA dependent ATPase, which unwinds DNA in a 5' to 3' direction [87]. Furthermore, Bach1 preferentially binds and unwinds DNA substrates that mimic an intermediate step in homologous recombination [88].…”

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confidence: 99%

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BRCA1 tumor suppressor network: focusing on its tail

Wang

2012

Cell & Bioscience

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Germline mutations of the BRCA1 tumor suppressor gene are a major cause of familial breast and ovarian cancer. BRCA1 plays critical roles in the DNA damage response that regulates activities of multiple repair and checkpoint pathways for maintaining genome stability. The BRCT domains of BRCA1 constitute a phospho-peptide binding domain recognizing a phospho-SPxF motif (S, serine; P, proline; × varies; F, phenylalanine). The BRCT domains are frequently targeted by clinically important mutations and most of these mutations disrupt the binding surface of the BRCT domains to phosphorylated peptides. The BRCT domain and its capability to bind phosphorylated protein is required for the tumor suppressor function of BRCA1. Through its BRCT phospho-binding ability BRCA1 forms at least three mutually exclusive complexes by binding to phosphorylated proteins Abraxas, Bach1 and CTIP. The A, B and C complexes, at lease partially undertake BRCA1's role in mechanisms of cell cycle checkpoint and DNA repair that maintain genome stability, thus may play important roles in BRCA1's tumor suppressor function.Germline mutations of the BRCA1 tumor suppressor gene are a major cause of familial breast and ovarian cancer [1,2]. BRCA1 plays critical roles in a number of diverse cellular processes that ensure genome integrity and the increase risk of breast and ovarian cancer caused by mutation of BRCA1 has been attributed to increased genomic instability. To safeguard genome, cells have evolved a defensive mechanism, called the DNA damage response (DDR), to coordinate multiple cellular responses including DNA repair, cell cycle checkpoint regulation, transcription, senescence or apoptosis etc., to counteract genotoxic stress [3][4][5][6]. BRCA1 appears to act as a central mediator of the cellular response to DNA damage that regulates the activities of multiple repair and checkpoint pathways [3,5,[7][8][9][10]. BRCA1 is a substrate of the central DNA damage response kinases ATM/ATR that control the DDR. It is required for homology directed repair, a pathway that facilitates error-free repair of double-strand breaks (DSBs) and resolution of stalled DNA replication forks through homologous recombination (HR) [9][10][11] as well as postreplicative repair in response to UV damage [12]. Recently it is suggested that much of BRCA1's role in maintaining genome stability is accounted for by its role in maintaining heterochromatin integrity via H2A ubiquitination [13].BRCA1 associates with multiple repair proteins and cell cycle regulators and such a capability to form multiple protein complexes contributes to its role in maintaining chromosome stability and tumor suppression (Figure 1). BRCA1 is a large protein of 1,863 amino acids. It contains two important domains at each end of the protein, a RING domain at the N-terminus and two BRCT domains at the C-terminus. Many clinically important mutations of BRCA1 gene frequently target these two domains. BRCA1 dimerizes with BARD1 through the RING domain present on each or the protein, forming...

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Section: Brca1-b Complex Is Required For Replication Stress Induced Cmentioning

confidence: 99%

mentioning

confidence: 99%

BRCA1 tumor suppressor network: focusing on its tail

Wang

2012

Cell & Bioscience

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“…D'Andrea [39] found FANCF to be transcriptionally silenced in sporadic ovarian tumors by methylation, and more importantly this was correlated with cisplatin sensitivity. Restoration of this pathway was found to be associated with demethylation of FANCF , leading to acquired cisplatinum resistance.…”

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confidence: 99%

Inactivation of the Tumor Suppressor Genes Causing the Hereditary Syndromes Predisposing to Head and Neck Cancer via Promoter Hypermethylation in Sporadic Head and Neck Cancers

Smith¹,

Mithani

Mydlarz³

et al. 2010

ORL

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Fanconi anemia (FA) and dyskeratosis congenita (DC) are rare inherited syndromes that cause head and neck squamous cell cancer (HNSCC). Prior studies of inherited forms of cancer have been extremely important in elucidating tumor suppressor genes inactivated in sporadic tumors. Here, we studied whether sporadic tumors have epigenetic silencing of the genes causing the inherited forms of HNSCC. Using bisulfite sequencing, we investigated the incidence of promoter hypermethylation of the 17 Fanconi- and DC-associated genes in sporadic HNSCC. Genes that only showed methylation in the tumor patients were chosen for quantitative methylation-specific PCR (qMSP) in a set of 45 tumor and 16 normal patients. Three gene promoters showed differences in methylation: FancB (FAAP95, FA core complex), FancJ (BRIP1, DNA Helicase/ATPase), and DKC1 (dyskeratin). Bisulfite sequencing revealed that only FancB and DKC1 showed no methylation in normal patients, yet the presence of promoter hypermethylation in tumor patients. On qMSP, 1/16 (6.25%) of the normal mucosal samples from non-cancer patients and 14/45 (31.1%) of the tumor patients demonstrated hypermethylation of the FancB locus (p < 0.05). These results suggest that inactivation of FancB may play a role in the pathogenesis of sporadic HNSCC.

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“…The key functional event in this pathway is the monoubiquitination of the repair effectors, FANCD2 and FANCI (28,29). Activation of this pathway culminates in repair of DNA crosslinks, UV-induced dimers, and double-strand breaks by homologous recombination and translesion synthesis (30).…”

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confidence: 99%

Monitoring a Nuclear Factor-κB Signature of Drug Resistance in Multiple Myeloma

Xiang

Remily-Wood

Oliveira

et al. 2011

Molecular & Cellular Proteomics

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The emergence of acquired drug resistance results from multiple compensatory mechanisms acting to prevent cell death. Simultaneous monitoring of proteins involved in drug resistance is a major challenge for both elucidation of the underlying biology and development of candidate biomarkers for assessment of personalized cancer therapy. Here, we have utilized an integrated analytical platform based on SDS-PAGE protein fractionation prior to liquid chromatography coupled to multiple reaction monitoring mass spectrometry, a versatile and powerful tool for targeted quantification of proteins in complex matrices, to evaluate a well-characterized model system of melphalan resistance in multiple myeloma (MM). Quantitative assays were developed to measure protein expression related to signaling events and biological processes relevant to melphalan resistance in multiple myeloma, specifically: nuclear factor-B subunits, members of the Bcl-2 family of apoptosis-regulating proteins, and Fanconi Anemia DNA repair components. SDS-PAGE protein fractionation prior to liquid chromatography coupled to multiple reaction monitoring methods were developed for quantification of these selected target proteins in amounts of material compatible with direct translation to clinical specimens (i.e. less than 50,000 cells). As proof of principle, both relative and absolute quantification were Multiple myeloma (MM)1 is an incurable malignancy of plasma cells harbored in the bone marrow, which is clinically characterized by secretion of monoclonal antibodies, calcium dysregulation, anemia, lytic bone lesions, and kidney damage. For five decades, therapeutic regimens for MM have included the alkylating agent, melphalan (p-di-2-chloroethylamino-1-phenylalanine, L-phenylalanine mustard, or L-PAM) (1). Therapy with L-PAM (alone or in combination with novel agents) remains the standard of care for transplant-ineligible patients and is the backbone of high-dose therapy associated with autologous stem cell transplant. Although MM patients initially respond to chemotherapy, treatment failure is inevitable because of the emergence of drug resistance. Because of the importance of detecting acquired drug resistance (ADR) for patient assessment and treatment, numerous mechanisms of ADR have been elucidated for MM in vitro, utilizing cell line models developed by chronic exposure to chemotherapy (2-7). These models were designed to identify potential drug targets to reverse ADR as well as to discover prognostic or chemopredictive biomarkers that could be translated to assessment of MM patients. These isogenic model systems clearly show that drug resistance is derived from multiple factors and that prediction of response can not depend on the measurement of one pathway.The biology of one such model of ADR, the 8226/LR5 cell line, selected by chronic exposure of RPMI-8226 MM cells to the DNA-damaging agent, melphalan, has been extensively characterized, leading to the identification of causative mechFrom the ‡Molecular Oncology, §Experimental Therapeutics,

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The Fanconi Anemia/BRCA Signaling Pathway: Disruption in Cisplatin-Sensitive Ovarian Cancers

Cited by 45 publications

References 9 publications

BRCA1 tumor suppressor network: focusing on its tail

BRCA1 tumor suppressor network: focusing on its tail

Inactivation of the Tumor Suppressor Genes Causing the Hereditary Syndromes Predisposing to Head and Neck Cancer via Promoter Hypermethylation in Sporadic Head and Neck Cancers

Monitoring a Nuclear Factor-κB Signature of Drug Resistance in Multiple Myeloma

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