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Thuy Vy Nguyen, Patrycja Pawlikowska, Virginie Firlej, Filippo Rosselli, Saïd Aoufouchi
B-lymphocytes in the bone marrow (BM) must generate a functional B-cell receptor and overcome the negative selection induced by reactivity with autoantigens. Two rounds of DNA recombination are required for the production of functional immunoglobulin heavy (Ig-HCs) and light (LCs) chains necessary for the continuation of B-lymphocyte development in the BM. Both rounds depend on the joint action of recombination activating gene-1 (RAG-1) and RAG-2 endonucleases with the DNA non-homologous end-joining pathway...
November 24, 2016: Scientific Reports
Julia Hess, Kristian Unger, Michael Orth, Ulrike Schötz, Lars Schüttrumpf, Verena Zangen, Igor Gimenez-Aznar, Agata Michna, Ludmila Schneider, Ramona Stamp, Martin Selmansberger, Herbert Braselmann, Ludwig Hieber, Guido A Drexler, Sebastian Kuger, Diana Klein, Verena Jendrossek, Anna A Friedl, Claus Belka, Horst Zitzelsberger, Kirsten Lauber
Radio (chemo) therapy is a crucial treatment modality for head and neck squamous cell carcinoma (HNSCC), but relapse is frequent, and the underlying mechanisms remain largely elusive. Therefore, novel biomarkers are urgently needed. Previously, we identified gains on 16q23-24 to be associated with amplification of the Fanconi anemia A (FancA) gene and to correlate with reduced progression-free survival after radiotherapy. Here, we analyzed the effects of FancA on radiation sensitivity in vitro, characterized the underlying mechanisms, and evaluated their clinical relevance...
November 17, 2016: Cancer Letters
Daniela Kramer, Nadine Stark, Ramona Schulz-Heddergott, Norman Erytch, Shelley Edmunds, Laura Roßmann, Holger Bastians, Nicole Concin, Ute M Moll, Matthias Dobbelstein
All current regimens for treating ovarian cancer center around carboplatin as standard first line. The HSP90 inhibitor ganetespib is currently being assessed in advanced clinical oncology trials. Thus, we tested the combined effects of ganetespib and carboplatin on a panel of 15 human ovarian cancer lines. Strikingly, the two drugs strongly synergized in cytotoxicity in tumor cells lacking wild-type p53. Mechanistically, ganetespib and carboplatin in combination, but not individually, induced persistent DNA damage causing massive global chromosome fragmentation...
November 11, 2016: Cell Death and Differentiation
Rui Zhang, Chang Liu, Yahan Niu, Ying Jing, Haiyang Zhang, Jin Wang, Jie Yang, Ke Zen, Junfeng Zhang, Chen-Yu Zhang, Donghai Li
The DNA damage response is critical for maintaining genome integrity and preventing damage to DNA due to endogenous and exogenous insults. Mitomycin C (MMC), a potent DNA cross-linker, is used as a chemotherapeutic agent because it causes DNA inter-strand cross-links (DNA ICLs) in cancer cells. While many microRNAs, which may serve as oncogenes or tumor suppressors, are grossly dysregulated in human cancers, little is known about their roles in MMC-treated lung cancer. Here, we report that miR-128-3p can attenuate repair of DNA ICLs by targeting SPTAN1 (αII Sp), resulting in cell cycle arrest and promoting chromosomal aberrations in lung cancer cells treated with MMC...
September 28, 2016: Oncotarget
Kris G Alavattam, Yasuko Kato, Ho-Su Sin, So Maezawa, Ian J Kowalski, Fan Zhang, Qishen Pang, Paul R Andreassen, Satoshi H Namekawa
Precise epigenetic regulation of the sex chromosomes is vital for the male germline. Here, we analyze meiosis in eight mouse models deficient for various DNA damage response (DDR) factors, including Fanconi anemia (FA) proteins. We reveal a network of FA and DDR proteins in which FA core factors FANCA, FANCB, and FANCC are essential for FANCD2 foci formation, whereas BRCA1 (FANCS), MDC1, and RNF8 are required for BRCA2 (FANCD1) and SLX4 (FANCP) accumulation on the sex chromosomes during meiosis. In addition, FA proteins modulate distinct histone marks on the sex chromosomes: FA core proteins and FANCD2 regulate H3K9 methylation, while FANCD2 and RNF8 function together to regulate H3K4 methylation independently of FA core proteins...
October 18, 2016: Cell Reports
Takahide Hayano, Hiroshi Matsui, Hirofumi Nakaoka, Nobuaki Ohtake, Kazuyoshi Hosomichi, Kazuhiro Suzuki, Ituro Inoue
Prostate cancer (PC) is the second most common cancer in men. Family history is the major risk factor for PC. Only two susceptibility genes were identified in PC, BRCA2 and HOXB13. A comprehensive search of germline variants for patients with PC has not been reported in Japanese families. In this study, we conducted exome sequencing followed by Sanger sequencing to explore responsible germline variants in 140 Japanese patients with PC from 66 families. In addition to known susceptibility genes, BRCA2 and HOXB13, we identified TRRAP variants in a mutually exclusive manner in seven large PC families (three or four patients per family)...
2016: PloS One
Nimrat Chatterjee, Yunfu Lin, John H Wilson
Almost 20 incurable neurodegenerative disorders are caused by trinucleotide repeat (TNR) expansion beyond a certain threshold, with disease time of onset and severity positively correlating with repeat length. Typically, long TNRs display a bias toward further expansion and repeats continue to expand not only during germline transmissions from parents to offspring, but also remain highly unstable in somatic tissues of patients. Hence, understanding TNR instability mechanisms sheds light on underlying disease pathology...
May 2016: Postdoc Journal: a Journal of Postdoctoral Research and Postdoctoral Affairs
W Du, S Amarachintha, A Wilson, Q Pang
Fanconi anemia (FA) is an inherited bone marrow (BM) failure syndrome with extremely high risk of leukemic transformation. Here we investigate the relationship between DNA damage response (DDR) and leukemogenesis using the Fanca knockout mouse model. We found that chronic exposure of the Fanca(-/-) hematopoietic stem cells (HSCs) to DNA cross-linking agent mitomycin C in vivo leads to diminished DDR, and the emergence/expansion of preleukemia stem cells (pre-LSCs). Surprisingly, although genetic correction of Fanca deficiency in the pre-LSCs restores DDR and reduces genomic instability but fails to prevent pre-LSC expansion or delay leukemia development in irradiated recipients...
August 29, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Li-Xian Chang, Ruan-Ruan Ren, Wen-Yu Yang, Jia-Yuan Zhang, Yang Wan, Tian-Feng Liu, Li Zhang, Xiao-Juan Chen, Shuai Zhu, Min Ruan, Xia Chen, Xiao-Ming Liu, Ben-Quan Qi, Ran-Ran Zhang, Yao Zou, Yu-Mei Chen, Xiao-Fan Zhu
OBJECTIVE: To investigate the association between clinical outcome and gene mutations in children with Fanconi anemia (FA). METHODS: A retrospective analysis was performed for the clinical data of six children with the same severity of FA and receiving the same treatment. At first, single cell gel electrophoresis and chromosome breakage induced by mitomycin C were performed for diagnosis. Then the gene detection kit for congenital bone marrow failure diseases or complementation test was used for genotyping of FA...
August 2016: Zhongguo Dang Dai Er Ke za Zhi, Chinese Journal of Contemporary Pediatrics
Wei Du, Surya Amarachintha, Ozlem Erden, Andrew Wilson, Qishen Pang
The Fanconi anemia (FA) pathway is involved in DNA damage and other cellular stress responses. We have investigated the role of the FA pathway in oncogenic stress response by employing an in vivo stress-response model expressing the Gadd45β-luciferase transgene. Using two inducible models of oncogenic activation (LSL-K-rasG12D and MycER), we show that hematopoietic stem and progenitor cells (HSPCs) from mice deficient for the FA core complex components Fanca or Fancc exhibit aberrant short-lived response to oncogenic insults...
August 5, 2016: Oncotarget
Min Jeong Chun, Sunshin Kim, Soo Kyung Hwang, Bong Sub Kim, Hyoun Geun Kim, Hae In Choi, Jong Heon Kim, Sung Ho Goh, Chang-Hun Lee
Fanconi anemia complementation group (FANC) proteins constitute the Fanconi Anemia (FA)/BRCA pathway that is activated in response to DNA interstrand crosslinks (ICLs). We previously performed yeast two-hybrid screening to identify novel FANC-interacting proteins and discovered that the alpha subunit of AMP-activated protein kinase (AMPKα1) was a candidate binding partner of the FANCG protein, which is a component of the FA nuclear core complex. We confirmed the interaction between AMPKα and both FANCG using co-immunoprecipitation experiments...
July 18, 2016: Oncotarget
Siobán B Keel, Angela Scott, Marilyn Sanchez-Bonilla, Phoenix A Ho, Suleyman Gulsuner, Colin C Pritchard, Janis L Abkowitz, Mary-Claire King, Tom Walsh, Akiko Shimamura
The clinical and histopathological distinctions between inherited versus acquired bone marrow failure and myelodysplastic syndromes are challenging. The identification of inherited bone marrow failure/myelodysplastic syndromes is critical to inform appropriate clinical management. To investigate whether a subset of pediatric and young adults undergoing transplant for aplastic anemia or myelodysplastic syndrome have germline mutations in bone marrow failure/myelodysplastic syndrome genes, we performed a targeted genetic screen of samples obtained between 1990-2012 from children and young adults with aplastic anemia or myelodysplastic syndrome transplanted at the Fred Hutchinson Cancer Research Center...
November 2016: Haematologica
Émilie L Dubois, Mariline Béliveau, Jean-Yves Masson
Fanconi Anemia is a rare autosomal recessive genetic disease with heterogenous phenotypes including myelosuppression, congenital malformations and heightened cancer predisposition. FA cells are highly sensitive to cross-linking agents. Since the 90's, at least 19 FANC proteins (FANCA to FANCT) have been identified as working together in a unique pathway detecting and triggering the repair of DNA crosslinks. Since then, the creation of animal models in various species (nematode, fruit fly, zebrafish and mouse) contributed to a better understanding of the physiopathology of the disease...
June 2016: Médecine Sciences: M/S
Min Jeong Chun, Soo Kyung Hwang, Hyoun Geun Kim, Sung-Ho Goh, Sunshin Kim, Chang-Hun Lee
Previous studies have linked the DNA damage response to mitotic progression machinery. Mitotic kinases, such as Aurora A kinase and Polo-like kinase, are involved in the phosphorylation of cell cycle regulators in response to DNA damage. Here, we investigated the potential involvement of Aurora A kinase in the activation of the Fanconi anemia (FA)/BRCA pathway, which participates in cellular response to DNA interstrand cross-link lesions (ICL). Initially, we detected interactions between Aurora A kinase and FANCA protein, one of the components of the FA nuclear core complex...
July 2016: FEBS Open Bio
Zdenek Kleibl, Vessela N Kristensen
The presence of breast cancer in any first-degree female relative in general nearly doubles the risk for a proband and the risk gradually increases with the number of affected relatives. Current advances in molecular oncology and oncogenetics may enable the identification of high-risk individuals with breast-cancer predisposition. The best-known forms of hereditary breast cancer (HBC) are caused by mutations in the high-penetrance genes BRCA1 and BRCA2. Other genes, including PTEN, TP53, STK11/LKB1, CDH1, PALB2, CHEK2, ATM, MRE11, RAD50, NBS1, BRIP1, FANCA, FANCC, FANCM, RAD51, RAD51B, RAD51C, RAD51D, and XRCC2 have been described as high- or moderate-penetrance breast cancer-susceptibility genes...
August 2016: Breast: Official Journal of the European Society of Mastology
Jingming Wang, Ukhyun Jo, So Young Joo, Hyungjin Kim
Mutations that deregulate protein degradation lead to human malignancies. The SCF ubiquitin E3 ligase complex degrades key oncogenic regulators, thereby limiting their oncogenic potential. FBW7 is a substrate recognition subunit of SCFFBW7 and is among the most commonly mutated ubiquitin-proteasome system proteins in cancer. FBW7-mutated cancer cells display increased genome instability, but the molecular mechanism by which FBW7 preserves genome integrity remains elusive. Here, we demonstrate that SCFFBW7 regulates the stability of FAAP20, a critical component of the Fanconi anemia (FA) DNA interstrand cross-link (ICL) repair pathway...
June 14, 2016: Oncotarget
Charles Lu, Peter Riedell, Christopher A Miller, Ian S Hagemann, Peter Westervelt, Bradley A Ozenberger, Michelle O'Laughlin, Vincent Magrini, Ryan T Demeter, Eric J Duncavage, Malachi Griffith, Obi L Griffith, Lukas D Wartman
We report the findings from a patient who presented with a concurrent mediastinal germ cell tumor (GCT) and acute myeloid leukemia (AML). Bone marrow pathology was consistent with a diagnosis of acute megakaryoblastic leukemia (AML M7), and biopsy of an anterior mediastinal mass was consistent with a nonseminomatous GCT. Prior studies have described associations between hematological malignancies, including AML M7 and nonseminomatous GCTs, and it was recently suggested that a common founding clone initiated both cancers...
January 2016: Cold Spring Harbor Molecular Case Studies
Rhea Sumpter, Shyam Sirasanagandla, Álvaro F Fernández, Yongjie Wei, Xiaonan Dong, Luis Franco, Zhongju Zou, Christophe Marchal, Ming Yeh Lee, D Wade Clapp, Helmut Hanenberg, Beth Levine
Fanconi anemia (FA) pathway genes are important tumor suppressors whose best-characterized function is repair of damaged nuclear DNA. Here, we describe an essential role for FA genes in two forms of selective autophagy. Genetic deletion of Fancc blocks the autophagic clearance of viruses (virophagy) and increases susceptibility to lethal viral encephalitis. Fanconi anemia complementation group C (FANCC) protein interacts with Parkin, is required in vitro and in vivo for clearance of damaged mitochondria, and decreases mitochondrial reactive oxygen species (ROS) production and inflammasome activation...
May 5, 2016: Cell
Ali Akbar Saffar Moghadam, Frouzandeh Mahjoubi, Nahid Reisi, Parvaneh Vosough
BACKGROUND & OBJECTIVES: Fanconi anaemia (FA) is a syndrome with a predisposition to bone marrow failure, congenital anomalies and malignancies. It is characterized by cellular hypersensitivity to cross-linking agents such as mitomycin C (MMC). In the present study, a new approach was selected to investigate FANCA (Fanconi anaemia complementation group A) gene in patients clinically diagnosed with cellular hypersensitivity to DNA cross-linking agent MMC. METHODS: Chromosomal breakage analysis was performed to prove the diagnosis of Fanconi anaemia in 318 families...
February 2016: Indian Journal of Medical Research
Giti Esmail Nia, Mahsa Fadaee, Robert Royer, Hossein Najmabadi, Mohammad R Akbari
BACKGROUND: Fanconi anemia (FA) is a rare genetic syndrome characterized by developmental defects, bone marrow failure, and a high cancer risk. FA is usually inherited as an autosomal recessive condition. This disease is genetically heterogeneous and mutations in 16 different genes have been identified in FA patients to date. An accurate diagnosis needs detection of pathogenic variations in the FA genes along with positive results from chromosome breakage test. METHODS: In this study, 48 families with at least 2 affected FA patients and positive chromosome breakage test were enrolled from the Iranian population...
April 2016: Archives of Iranian Medicine
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