Luc Friboulet, Sophie Postel-Vinay, Tony Sourisseau, Julien Adam, Annabelle Stoclin, Florence Ponsonnailles, Nicolas Dorvault, Frédéric Commo, Patrick Saulnier, Sophie Salome-Desmoulez, Géraldine Pottier, Fabrice André, Guido Kroemer, Jean-Charles Soria, Ken André Olaussen
ERCC1 (excision repair cross-complementation group 1) plays essential roles in the removal of DNA intrastrand crosslinks by nucleotide excision repair, and that of DNA interstrand crosslinks by the Fanconi anemia (FA) pathway and homology-directed repair processes (HDR). The function of ERCC1 thus impacts on the DNA damage response (DDR), particularly in anticancer therapy when DNA damaging agents are employed. ERCC1 expression has been proposed as a predictive biomarker of the response to platinum-based therapy...
October 15, 2013: Cell Cycle
Grzegorz Nalepa, Rikki Enzor, Zejin Sun, Christophe Marchal, Su-Jung Park, Yanzhu Yang, Laura Tedeschi, Stephanie Kelich, Helmut Hanenberg, D Wade Clapp
Fanconi anemia (FA) is a heterogenous genetic disease with a high risk of cancer. The FA proteins are essential for interphase DNA damage repair; however, it is incompletely understood why FA-deficient cells also develop gross aneuploidy, leading to cancer. Here, we systematically evaluated the role of the FA proteins in chromosome segregation through functional RNAi screens and analysis of primary cells from patients with FA. We found that FA signaling is essential for the spindle assembly checkpoint and is therefore required for high-fidelity chromosome segregation and prevention of aneuploidy...
September 2013: Journal of Clinical Investigation
Dorian R A Swarts, Leander Van Neste, Mieke E R Henfling, Ivo Eijkenboom, Paul P Eijk, Marie-Louise van Velthuysen, Aryan Vink, Marco Volante, Bauke Ylstra, Wim Van Criekinge, Manon van Engeland, Frans C S Ramaekers, Ernst-Jan M Speel
Pulmonary carcinoids comprise a well-differentiated subset of neuroendocrine tumors usually associated with a favorable prognosis, but mechanisms underlying disease progression are poorly understood. In an explorative approach to identify pathways associated with progression, we compared gene expression profiles of tumors from five patients with a favorable and five with a poor disease outcome. Differentially expressed genes were validated using quantitative real-time PCR on 65 carcinoid tumors, in combination with survival analysis...
December 2013: Carcinogenesis
Sunshin Kim, Soo Kyung Hwang, Mihee Lee, Heejin Kwak, Kook Son, Jiha Yang, Sung Hak Kim, Chang-Hun Lee
Fanconi anemia (FA) proteins are known to play roles in the cellular response to DNA interstrand cross-linking lesions; however, several reports have suggested that FA proteins play additional roles. To elucidate novel functions of FA proteins, we used yeast two-hybrid screening to identify binding partners of the Fanconi anemia complementation group A (FANCA) protein. The candidate proteins included never-in-mitosis-gene A (NIMA)-related kinase 2 (Nek2), which functions in the maintenance of centrosome integrity...
September 2013: International Journal of Biochemistry & Cell Biology
Thiyam Ramsing Singh, Abdullah Mahmood Ali, Manikandan Paramasivam, Arun Pradhan, Kebola Wahengbam, Michael M Seidman, Amom Ruhikanta Meetei
Fanconi anemia (FA) is a genome instability syndrome that has been associated with both cancer predisposition and bone marrow failure. FA proteins are involved in cellular response to replication stress in which they coordinate DNA repair with DNA replication and cell-cycle progression. One regulator of the replication stress response is the ATP-dependent DNA translocase FANCM, which we have shown to be hyperphosphorylated in response to various genotoxic agents. However, the significance of this phosphorylation remained unclear...
July 15, 2013: Cancer Research
Audesh Bhat, Parker L Andersen, Zhoushuai Qin, Wei Xiao
It has been long speculated that mammalian Rev3 plays an important, yet unknown role(s) during mammalian development, as deletion of Rev3 causes embryonic lethality in mice, whereas no other translesion DNA synthesis polymerases studied to date are required for mouse embryo development. Here, we report that both subunits of Polζ (Rev3 and Rev7) show an unexpected increase in expression during G(2)/M phase, but they localize independently in mitotic cells. Experimental depletion of Rev3 results in a significant increase in anaphase bridges, chromosomal breaks/gaps and common fragile site (CFS) expression, whereas Rev7 depletion primarily causes lagging chromosome defect with no sign of CFS expression...
February 1, 2013: Nucleic Acids Research
Shilpy Sharma, Corey M Helchowski, Christine E Canman
Cancer cells display numerous abnormal characteristics which are initiated and maintained by elevated mutation rates and genome instability. Chromosomal DNA is continuously surveyed for the presence of damage or blocked replication forks by the DNA Damage Response (DDR) network. The DDR is complex and includes activation of cell cycle checkpoints, DNA repair, gene transcription, and induction of apoptosis. Duplicating a damaged genome is associated with elevated risks to fork collapse and genome instability...
March 2013: Mutation Research
Shane R Stecklein, Easwari Kumaraswamy, Fariba Behbod, Wenjia Wang, Vamsee Chaguturu, Lisa M Harlan-Williams, Roy A Jensen
Expression of functional breast cancer susceptibility gene 1 (BRCA1) in human breast and ovarian cancers is associated with resistance to platinum-based chemotherapeutics and poly(ADP ribose) polymerase (PARP) inhibitors. BRCA1 is a nuclear tumor suppressor that is critical for resolving double-strand DNA breaks (DSBs) and interstrand crosslinks (ICLs) by homologous recombination (HR). In vitro, animal and human clinical data have demonstrated that BRCA1-deficient cancers are highly sensitive to ICL-inducing chemotherapeutic agents, are amenable to synthetic lethal approaches that exploit defects in DSB/ICL repair, and may be associated with improved survival...
August 21, 2012: Proceedings of the National Academy of Sciences of the United States of America
Marlis Frankenberg-Schwager, Anke Gregus
PURPOSE: Mammography X-rays are known to induce DNA double-strand breaks (DSB) whose error-free recombinational repair requires the function of the tumour repressor genes BRCA1 (breast-cancer-associated gene 1) and BRCA2 (breast-cancer-associated gene 2). Since un- or misrepaired DSB lead to chromosomal anomalies which may promote the development of breast cancer, we have studied the potential of mammography X-rays for immediate and delayed induction of chromosomal anomalies in human primary fibroblasts from BRCA1 and BRCA2 mutation carriers...
November 2012: International Journal of Radiation Biology
Jie Li, Takuma Shiraki, Kazuhiko Igarashi
The transcriptional repressor Bach1 mediates various stress responses. Despite its role in transcription, Bach1 is predominantly exported to the cytoplasm in a Crm1-dependent manner, but the functional role of its cytoplasmic retention is still unclear. We found that Bach1 was also excluded from mitotic chromatin by a C-terminal cytoplasmic localization sequence dependent and leptomycin B sensitive process. Bach1 depletion resulted in disordered mitotic chromosome alignment, which was rescued by Bach1 mutants lacking the BTB or DNA binding domains, suggesting its transcription-independent mechanism...
February 17, 2012: FEBS Letters
Xiomaris M Cotto-Rios, Mathew J K Jones, Tony T Huang
Tight regulation of the cell cycle and DNA repair machinery is essential for maintaining genome stability. The APC/CCdh1 ubiquitin ligase complex is a key regulator of protein stability during the G 1 phase of the cell cycle. APC/CCdh1 regulates and promotes the degradation of proteins involved in both cell cycle regulation and DNA repair. In a recent study, we identified a novel APC/CCdh1 substrate, the ubiquitin protease USP1. USP1 is a critical regulator of both the Fanconi anemia (FA) and translesion synthesis (TLS) DNA repair pathways...
December 1, 2011: Cell Cycle
Kok Lung Chan, Ian D Hickson
Recent data indicate an unexpected requirement for proteins that were hitherto considered to be dedicated to DNA repair to facilitate the faithful disjunction of sister chromatids in anaphase. These include the Bloom's syndrome gene product, BLM and its partners, as well as a number of proteins that are important for preventing Fanconi anemia (FA) in man. As part of an analysis of the roles of these proteins in mitosis, we identified a novel class of anaphase bridge structure, called an ultra-fine anaphase bridge (UFB)...
October 2011: Seminars in Cell & Developmental Biology
Songmin Ying, Ian D Hickson
The maintenance of genome stability is critical for the suppression of cancer and premature ageing. The maintenance of the human genome requires hundreds of proteins involved in DNA repair, DNA replication, chromosome segregation and cell cycle checkpoint responses. A number of genetic disorders exist in man where a breakdown in genome maintenance is associated with cancer predisposition. Amongst these are Bloom's syndrome (BS) and Fanconi anaemia (FA). The BS and FA gene products co-operate in the repair of damaged DNA...
April 2011: International Journal of Hematology
Patrizia Vinciguerra, Susana A Godinho, Kalindi Parmar, David Pellman, Alan D D'Andrea
Fanconi anemia (FA) is a genomic instability disorder characterized by bone marrow failure and cancer predisposition. FA is caused by mutations in any one of several genes that encode proteins cooperating in a repair pathway and is required for cellular resistance to DNA crosslinking agents. Recent studies suggest that the FA pathway may also play a role in mitosis, since FANCD2 and FANCI, the 2 key FA proteins, are localized to the extremities of ultrafine DNA bridges (UFBs), which link sister chromatids during cell division...
November 2010: Journal of Clinical Investigation
Kok Lung Chan, Ian D Hickson
No abstract text is available yet for this article.
October 1, 2009: Cell Cycle
Valeria Naim, Filippo Rosselli
Fanconi anemia (FA) is a chromosome instability syndrome characterized by progressive bone marrow failure and cancer proneness. The proteins mutated in FA constitute the so-called FANC/BRCA pathway, involved in DNA replication and damage response. However, it is not completely understood how the FANC proteins perform their functions and maintain chromosome stability. Two recently published works reported that FANCD2 localizes to discrete sites on mitotic chromosomes, as consequence of replication fork stalling...
September 15, 2009: Cell Cycle
Kok Lung Chan, Timea Palmai-Pallag, Songmin Ying, Ian D Hickson
Several inherited syndromes in humans are associated with cancer predisposition. The gene products defective in two of these disorders, BLM (a helicase defective in Bloom's syndrome) and FANC A-N (defective in Fanconi anaemia), associate in a multienzyme complex called BRAFT. How these proteins suppress tumorigenesis remains unclear, although both conditions are associated with chromosome instability. Here we show that the Fanconi anaemia proteins FANCD2 and FANCI specifically associate with common fragile site loci irrespective of whether the chromosome is broken...
June 2009: Nature Cell Biology
Valeria Naim, Filippo Rosselli
Loss-of-function of caretaker genes characterizes a group of cancer predisposition diseases that feature cellular hypersensitivity to DNA damage and chromosome fragility; this group includes Fanconi anaemia and Bloom syndrome. The products of the 13 FANC genes (mutated in Fanconi anaemia), which constitute the 'FANC' pathway, and BLM (the RecQ helicase mutated in Bloom syndrome) are thought to collaborate during the S phase of the cell cycle, preventing chromosome instability. Recently, BLM has been implicated in the completion of sister chromatid separation during mitosis, a complex process in which precise regulation and execution is crucial to preserve genomic stability...
June 2009: Nature Cell Biology
Younghoon Kee, Jung Min Kim, Alan D D'Andrea, Alan D'Andrea
The 13 Fanconi anemia (FA) proteins cooperate in a common DNA repair pathway. Eight of these proteins are assembled into a multisubunit E3 ligase called the FA core complex. During S phase, the FA core complex is loaded by the FANCM protein into chromatin where it monoubiquitinates its substrates. In mitosis, the FA core complex is released from FANCM by an unknown mechanism. Here we show that FANCM is hyperphosphorylated and degraded during mitosis. beta-TRCP and Plk1 are the key regulators of FANCM degradation...
March 1, 2009: Genes & Development
Hocine W Mankouri, Hien-Ping Ngo, Ian D Hickson
Esc2 is a member of the RENi family of SUMO-like domain proteins and is implicated in gene silencing in Saccharomyces cerevisiae. Here, we identify a dual role for Esc2 during S-phase in mediating both intra-S-phase DNA damage checkpoint signaling and preventing the accumulation of Rad51-dependent homologous recombination repair (HRR) intermediates. These roles are qualitatively similar to those of Sgs1, the yeast ortholog of the human Bloom's syndrome protein, BLM. However, whereas mutation of either ESC2 or SGS1 leads to the accumulation of unprocessed HRR intermediates in the presence of MMS, the accumulation of these structures in esc2 (but not sgs1) mutants is entirely dependent on Mph1, a protein that shows structural similarity to the Fanconi anemia group M protein (FANCM)...
March 2009: Molecular Biology of the Cell
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