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winfried edelmann

Sohail Jahid, Jian Sun, Ozkan Gelincik, Pedro Blecua, Winfried Edelmann, Raju Kucherlapati, Kathy Zhou, Maria Jasin, Zeynep H Gümüş, Steven M Lipkin
Homologous recombination (HR) enables precise DNA repair after DNA double strand breaks (DSBs) using identical sequence templates, whereas homeologous recombination (HeR) uses only partially homologous sequences. Homeologous recombination introduces mutations through gene conversion and genomic deletions through single-strand annealing (SSA). DNA mismatch repair (MMR) inhibits HeR, but the roles of mammalian MMR MutL homologues (MLH1, PMS2 and MLH3) proteins in HeR suppression are poorly characterized. Here, we demonstrate that mouse embryonic fibroblasts (MEFs) carrying Mlh1 , Pms2 , and Mlh3 mutations have higher HeR rates, by using 7,863 uniquely mapping paired direct repeat sequences (DRs) in the mouse genome as endogenous gene conversion and SSA reporters...
September 22, 2017: Oncotarget
Chun-Chin Chen, Elena Avdievich, Yongwei Zhang, Yu Zhang, Kaichun Wei, Kyeryoung Lee, Winfried Edelmann, Maria Jasin, Jeannine R LaRocque
DNA double-strand breaks (DSBs) can be repaired through several mechanisms, including homologous recombination (HR). While HR between identical sequences is robust in mammalian cells, HR between diverged sequences is suppressed by DNA mismatch-repair (MMR) components such as MSH2. Exonuclease I (EXO1) interacts with the MMR machinery and has been proposed to act downstream of the mismatch recognition proteins in mismatch correction. EXO1 has also been shown to participate in extensive DSB end resection, an initial step in the HR pathway...
September 2017: DNA Repair
Sohail Jahid, Jian Sun, Ozkan Gelincik, Pedro Blecua, Winfried Edelmann, Raju Kucherlapati, Kathy Zhou, Maria Jasin, Zeynep H Gümüş, Steven M Lipkin
Homologous recombination (HR) enables precise DNA repair after DNA double strand breaks (DSBs) using identical sequence templates, whereas homeologous recombination (HeR) uses only partially homologous sequences. Homeologous recombination introduces mutations through gene conversion and genomic deletions through single-strand annealing (SSA). DNA mismatch repair (MMR) inhibits HeR, but the roles of mammalian MMR MutL homologues (MLH1, PMS2 and MLH3) proteins in HeR suppression are poorly characterized. Here, we demonstrate that mouse embryonic fibroblasts (MEFs) carrying Mlh1, Pms2, and Mlh3 mutations have higher HeR rates, by using 7,863 uniquely mapping paired direct repeat sequences (DRs) in the mouse genome as endogenous gene conversion and SSA reporters...
May 10, 2017: Oncotarget
Philipp S Wild, Janine F Felix, Arne Schillert, Alexander Teumer, Ming-Huei Chen, Maarten J G Leening, Uwe Völker, Vera Großmann, Jennifer A Brody, Marguerite R Irvin, Sanjiv J Shah, Setia Pramana, Wolfgang Lieb, Reinhold Schmidt, Alice V Stanton, Dörthe Malzahn, Albert Vernon Smith, Johan Sundström, Cosetta Minelli, Daniela Ruggiero, Leo-Pekka Lyytikäinen, Daniel Tiller, J Gustav Smith, Claire Monnereau, Marco R Di Tullio, Solomon K Musani, Alanna C Morrison, Tune H Pers, Michael Morley, Marcus E Kleber, Jayashri Aragam, Emelia J Benjamin, Joshua C Bis, Egbert Bisping, Ulrich Broeckel, Susan Cheng, Jaap W Deckers, Fabiola Del Greco M, Frank Edelmann, Myriam Fornage, Lude Franke, Nele Friedrich, Tamara B Harris, Edith Hofer, Albert Hofman, Jie Huang, Alun D Hughes, Mika Kähönen, Knhi Investigators, Jochen Kruppa, Karl J Lackner, Lars Lannfelt, Rafael Laskowski, Lenore J Launer, Margrét Leosdottir, Honghuang Lin, Cecilia M Lindgren, Christina Loley, Calum A MacRae, Deborah Mascalzoni, Jamil Mayet, Daniel Medenwald, Andrew P Morris, Christian Müller, Martina Müller-Nurasyid, Stefania Nappo, Peter M Nilsson, Sebastian Nuding, Teresa Nutile, Annette Peters, Arne Pfeufer, Diana Pietzner, Peter P Pramstaller, Olli T Raitakari, Kenneth M Rice, Fernando Rivadeneira, Jerome I Rotter, Saku T Ruohonen, Ralph L Sacco, Tandaw E Samdarshi, Helena Schmidt, Andrew S P Sharp, Denis C Shields, Rossella Sorice, Nona Sotoodehnia, Bruno H Stricker, Praveen Surendran, Simon Thom, Anna M Töglhofer, André G Uitterlinden, Rolf Wachter, Henry Völzke, Andreas Ziegler, Thomas Münzel, Winfried März, Thomas P Cappola, Joel N Hirschhorn, Gary F Mitchell, Nicholas L Smith, Ervin R Fox, Nicole D Dueker, Vincent W V Jaddoe, Olle Melander, Martin Russ, Terho Lehtimäki, Marina Ciullo, Andrew A Hicks, Lars Lind, Vilmundur Gudnason, Burkert Pieske, Anthony J Barron, Robert Zweiker, Heribert Schunkert, Erik Ingelsson, Kiang Liu, Donna K Arnett, Bruce M Psaty, Stefan Blankenberg, Martin G Larson, Stephan B Felix, Oscar H Franco, Tanja Zeller, Ramachandran S Vasan, Marcus Dörr
BACKGROUND: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function...
May 1, 2017: Journal of Clinical Investigation
Juraj Kokavec, Tomas Zikmund, Filipp Savvulidi, Vojtech Kulvait, Winfried Edelmann, Arthur I Skoultchi, Tomas Stopka
The imitation switch nuclear ATPase Smarca5 (Snf2h) is one of the most conserved chromatin remodeling factors. It exists in a variety of oligosubunit complexes that move DNA with respect to the histone octamer to generate regularly spaced nucleosomal arrays. Smarca5 interacts with different accessory proteins and represents a molecular motor for DNA replication, repair, and transcription. We deleted Smarca5 at the onset of definitive hematopoiesis (Vav1-iCre) and observed that animals die during late fetal development due to anemia...
June 2017: Stem Cells
Yongliang Zhang, Jennifer T Fox, Young-Un Park, Gene Elliott, Ganesha Rai, Mengli Cai, Srilatha Sakamuru, Ruili Huang, Menghang Xia, Kyeryoung Lee, Min Ho Jeon, Bijoy P Mathew, Hee Dong Park, Winfried Edelmann, Chan Young Park, Sung You Hong, David Maloney, Kyungjae Myung
Impairing the division of cancer cells with genotoxic small molecules has been a primary goal to develop chemotherapeutic agents. However, DNA mismatch repair (MMR)-deficient cancer cells are resistant to most conventional chemotherapeutic agents. Here we have identified baicalein as a small molecule that selectively kills MutSα-deficient cancer cells. Baicalein binds preferentially to mismatched DNA and induces a DNA damage response in a MMR-dependent manner. In MutSα-proficient cells, baicalein binds to MutSα to dissociate CHK2 from MutSα leading to S-phase arrest and cell survival...
July 15, 2016: Cancer Research
Yuji Eso, Atsushi Takai, Tomonori Matsumoto, Tadashi Inuzuka, Takahiro Horie, Koh Ono, Shinji Uemoto, Kyeryoung Lee, Winfried Edelmann, Tsutomu Chiba, Hiroyuki Marusawa
Inflammation predisposes to tumorigenesis in various organs by potentiating a susceptibility to genetic aberrations. The mechanism underlying the enhanced genetic instability through chronic inflammation, however, is not clear. Here, we demonstrated that TNFα stimulation induced transcriptional downregulation of MSH2, a member of the mismatch repair family, via NF-κB-dependent miR-21 expression in hepatocytes. Liver cancers developed in ALB-MSH2(-) (/) (-)AID(+), ALB-MSH2(-) (/) (-), and ALB-AID(+) mice, in which MSH2 is deficient and/or activation-induced cytidine deaminase (AICDA) is expressed in cells with albumin-producing hepatocytes...
August 1, 2016: Cancer Research
Shuying He, Saima Limi, Rebecca S McGreal, Qing Xie, Lisa A Brennan, Wanda Lee Kantorow, Juraj Kokavec, Romit Majumdar, Harry Hou, Winfried Edelmann, Wei Liu, Ruth Ashery-Padan, Jiri Zavadil, Marc Kantorow, Arthur I Skoultchi, Tomas Stopka, Ales Cvekl
Ocular lens morphogenesis is a model for investigating mechanisms of cellular differentiation, spatial and temporal gene expression control, and chromatin regulation. Brg1 (Smarca4) and Snf2h (Smarca5) are catalytic subunits of distinct ATP-dependent chromatin remodeling complexes implicated in transcriptional regulation. Previous studies have shown that Brg1 regulates both lens fiber cell differentiation and organized degradation of their nuclei (denucleation). Here, we employed a conditional Snf2h(flox) mouse model to probe the cellular and molecular mechanisms of lens formation...
June 1, 2016: Development
Ester Borras, F Anthony San Lucas, Kyle Chang, Ruoji Zhou, Gita Masand, Jerry Fowler, Maureen E Mork, Y Nancy You, Melissa W Taggart, Florencia McAllister, David A Jones, Gareth E Davies, Winfried Edelmann, Erik A Ehli, Patrick M Lynch, Ernest T Hawk, Gabriel Capella, Paul Scheet, Eduardo Vilar
The molecular basis of the adenoma-to-carcinoma transition has been deduced using comparative analysis of genetic alterations observed through the sequential steps of intestinal carcinogenesis. However, comprehensive genomic analyses of adenomas and at-risk mucosa are still lacking. Therefore, our aim was to characterize the genomic landscape of colonic at-risk mucosa and adenomas. We analyzed the mutation profile and copy number changes of 25 adenomas and adjacent mucosa from 12 familial adenomatous polyposis patients using whole-exome sequencing and validated allelic imbalances (AI) in 37 adenomas using SNP arrays...
June 2016: Cancer Prevention Research
Kyeryoung Lee, Elena Tosti, Winfried Edelmann
Germline mutations in DNA mismatch repair (MMR) genes are the cause of hereditary non-polyposis colorectal cancer/Lynch syndrome (HNPCC/LS) one of the most common cancer predisposition syndromes, and defects in MMR are also prevalent in sporadic colorectal cancers. In the past, the generation and analysis of mouse lines with knockout mutations in all of the known MMR genes has provided insight into how loss of individual MMR genes affects genome stability and contributes to cancer susceptibility. These studies also revealed essential functions for some of the MMR genes in B cell maturation and fertility...
February 2016: DNA Repair
Britta Will, Thomas O Vogler, Swathi Narayanagari, Boris Bartholdy, Tihomira I Todorova, Mariana da Silva Ferreira, Jiahao Chen, Yiting Yu, Jillian Mayer, Laura Barreyro, Luis Carvajal, Daniela Ben Neriah, Michael Roth, Johanna van Oers, Sonja Schaetzlein, Christine McMahon, Winfried Edelmann, Amit Verma, Ulrich Steidl
Modest transcriptional changes caused by genetic or epigenetic mechanisms are frequent in human cancer. Although loss or near-complete loss of the hematopoietic transcription factor PU.1 induces acute myeloid leukemia (AML) in mice, a similar degree of PU.1 impairment is exceedingly rare in human AML; yet, moderate PU.1 inhibition is common in AML patients. We assessed functional consequences of modest reductions in PU.1 expression on leukemia development in mice harboring DNA lesions resembling those acquired during human stem cell aging...
October 2015: Nature Medicine
Katrin Rein, Diana A Yanez, Berta Terré, Lluís Palenzuela, Suvi Aivio, Kaichun Wei, Winfried Edelmann, Jeremy M Stark, Travis H Stracker
The maintenance of genome stability is critical for the suppression of diverse human pathologies that include developmental disorders, premature aging, infertility and predisposition to cancer. The DNA damage response (DDR) orchestrates the appropriate cellular responses following the detection of lesions to prevent genomic instability. The MRE11 complex is a sensor of DNA double strand breaks (DSBs) and plays key roles in multiple aspects of the DDR, including DNA end resection that is critical for signaling and DNA repair...
September 3, 2015: Nucleic Acids Research
Huanhuan Joyce Chen, Jian Sun, Zhiliang Huang, Harry Hou, Myra Arcilla, Nikolai Rakhilin, Daniel J Joe, Jiahn Choi, Poornima Gadamsetty, Jeff Milsom, Govind Nandakumar, Randy Longman, Xi Kathy Zhou, Robert Edwards, Jonlin Chen, Kai Yuan Chen, Pengcheng Bu, Lihua Wang, Yitian Xu, Robert Munroe, Christian Abratte, Andrew D Miller, Zeynep H Gümüş, Michael Shuler, Nozomi Nishimura, Winfried Edelmann, Xiling Shen, Steven M Lipkin
Current orthotopic xenograft models of human colorectal cancer (CRC) require surgery and do not robustly form metastases in the liver, the most common site clinically. CCR9 traffics lymphocytes to intestine and colorectum. We engineered use of the chemokine receptor CCR9 in CRC cell lines and patient-derived cells to create primary gastrointestinal (GI) tumors in immunodeficient mice by tail-vein injection rather than surgery. The tumors metastasize inducibly and robustly to the liver. Metastases have higher DKK4 and NOTCH signaling levels and are more chemoresistant than paired subcutaneous xenografts...
June 2015: Nature Biotechnology
Benedikt Kortüm, Christoph Campregher, Michaela Lang, Vineeta Khare, Matthias Pinter, Rayko Evstatiev, Gerald Schmid, Martina Mittlböck, Theresa Scharl, Melanie H Kucherlapati, Winfried Edelmann, Christoph Gasche
OBJECTIVE: Lynch syndrome is caused by germline mutations in DNA mismatch repair genes leading to microsatellite instability (MSI) and colorectal cancer. Mesalazine, commonly used for the treatment of UC, reduces MSI in vitro. Here, we tested natural compounds for such activity and applied mesalazine and thymoquinone in a Msh2(loxP/loxP) Villin-Cre mouse model for Lynch syndrome. DESIGN: Flow cytometry was used for quantitation of mutation rates at a CA13 microsatellite in human colon cancer (HCT116) cells that had been stably transfected with pIREShyg2-enhanced green fluorescent protein/CA13, a reporter for frameshift mutations...
December 2015: Gut
Elena Tosti, Joseph A Katakowski, Sonja Schaetzlein, Hyun-Soo Kim, Colm J Ryan, Michael Shales, Assen Roguev, Nevan J Krogan, Deborah Palliser, Michael-Christopher Keogh, Winfried Edelmann
BACKGROUND: The evolutionarily conserved DNA mismatch repair (MMR) system corrects base-substitution and insertion-deletion mutations generated during erroneous replication. The mutation or inactivation of many MMR factors strongly predisposes to cancer, where the resulting tumors often display resistance to standard chemotherapeutics. A new direction to develop targeted therapies is the harnessing of synthetic genetic interactions, where the simultaneous loss of two otherwise non-essential factors leads to reduced cell fitness or death...
2014: Genome Medicine
Stefan Pilz, Frank Edelmann, Andreas Meinitzer, Götz Gelbrich, Ufuk Döner, Hans-Dirk Düngen, Andreas Tomaschitz, Katharina Kienreich, Martin Gaksch, André Duvinage, Raoul Stahrenberg, Jan Kunde, Albrecht Schmidt, Winfried März, Rolf Wachter, Burkert Pieske
BACKGROUND: Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and homoarginine are considered to modulate nitric oxide synthesis. We evaluated whether ADMA, SDMA, and homoarginine are associated with diastolic dysfunction. METHODS AND RESULTS: We investigated primary care patients at cardiovascular risk with preserved left ventricular ejection fraction from the multicenter DIAST-CHF study. We measured serum concentrations of ADMA, SDMA, and homoarginine and performed standardized echocardiographic examinations...
December 2014: Journal of Cardiac Failure
Stefan M Woerner, Elena Tosti, Yan P Yuan, Matthias Kloor, Peer Bork, Winfried Edelmann, Johannes Gebert
Different DNA mismatch repair (MMR)-deficient mouse strains have been developed as models for the inherited cancer predisposing Lynch syndrome. It is completely unresolved, whether coding mononucleotide repeat (cMNR) gene mutations in these mice can contribute to intestinal tumorigenesis and whether MMR-deficient mice are a suitable molecular model of human microsatellite instability (MSI)-associated intestinal tumorigenesis. A proof-of-principle study was performed to identify mouse cMNR-harboring genes affected by insertion/deletion mutations in MSI murine intestinal tumors...
November 2015: Molecular Carcinogenesis
Antoaneta Belcheva, Thergiory Irrazabal, Susan J Robertson, Catherine Streutker, Heather Maughan, Stephen Rubino, Eduardo H Moriyama, Julia K Copeland, Anu Surendra, Sachin Kumar, Blerta Green, Kaoru Geddes, Rossanna C Pezo, William W Navarre, Michael Milosevic, Brian C Wilson, Stephen E Girardin, Thomas M S Wolever, Winfried Edelmann, David S Guttman, Dana J Philpott, Alberto Martin
The etiology of colorectal cancer (CRC) has been linked to deficiencies in mismatch repair and adenomatous polyposis coli (APC) proteins, diet, inflammatory processes, and gut microbiota. However, the mechanism through which the microbiota synergizes with these etiologic factors to promote CRC is not clear. We report that altering the microbiota composition reduces CRC in APC(Min/+)MSH2(-/-) mice, and that a diet reduced in carbohydrates phenocopies this effect. Gut microbes did not induce CRC in these mice through an inflammatory response or the production of DNA mutagens but rather by providing carbohydrate-derived metabolites such as butyrate that fuel hyperproliferation of MSH2(-/-) colon epithelial cells...
July 17, 2014: Cell
Hyun-Soo Kim, Rituparna Mukhopadhyay, Scott B Rothbart, Andrea C Silva, Vincent Vanoosthuyse, Ernest Radovani, Thomas Kislinger, Assen Roguev, Colm J Ryan, Jiewei Xu, Harlizawati Jahari, Kevin G Hardwick, Jack F Greenblatt, Nevan J Krogan, Jeffrey S Fillingham, Brian D Strahl, Eric E Bouhassira, Winfried Edelmann, Michael-Christopher Keogh
Condensin is a central regulator of mitotic genome structure with mutants showing poorly condensed chromosomes and profound segregation defects. Here, we identify NCT, a complex comprising the Nrc1 BET-family tandem bromodomain protein (SPAC631.02), casein kinase II (CKII), and several TAFs, as a regulator of condensin function. We show that NCT and condensin bind similar genomic regions but only briefly colocalize during the periods of chromosome condensation and decondensation. This pattern of NCT binding at the core centromere, the region of maximal condensin enrichment, tracks the abundance of acetylated histone H4, as regulated by the Hat1-Mis16 acetyltransferase complex and recognized by the first Nrc1 bromodomain...
March 13, 2014: Cell Reports
Felix Dietlein, Lisa Thelen, Mladen Jokic, Ron D Jachimowicz, Laura Ivan, Gero Knittel, Uschi Leeser, Johanna van Oers, Winfried Edelmann, Lukas C Heukamp, H Christian Reinhardt
Here, we use a large-scale cell line-based approach to identify cancer cell-specific mutations that are associated with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) dependence. For this purpose, we profiled the mutational landscape across 1,319 cancer-associated genes of 67 distinct cell lines and identified numerous genes involved in homologous recombination-mediated DNA repair, including BRCA1, BRCA2, ATM, PAXIP, and RAD50, as being associated with non-oncogene addiction to DNA-PKcs. Mutations in the mismatch repair gene MSH3, which have been reported to occur recurrently in numerous human cancer entities, emerged as the most significant predictors of DNA-PKcs addiction...
May 2014: Cancer Discovery
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