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UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors.
Jachimowicz, Ron D; Beleggia, Filippo; Isensee, Jörg; Velpula, Bhagya Bhavana; Goergens, Jonas; Bustos, Matias A; Doll, Markus A; Shenoy, Anjana; Checa-Rodriguez, Cintia; Wiederstein, Janica Lea; Baranes-Bachar, Keren; Bartenhagen, Christoph; Hertwig, Falk; Teper, Nizan; Nishi, Tomohiko; Schmitt, Anna; Distelmaier, Felix; Lüdecke, Hermann-Josef; Albrecht, Beate; Krüger, Marcus; Schumacher, Björn; Geiger, Tamar; Hoon, Dave S B; Huertas, Pablo; Fischer, Matthias; Hucho, Tim; Peifer, Martin; Ziv, Yael; Reinhardt, H Christian; Wieczorek, Dagmar; Shiloh, Yosef.
  • Jachimowicz RD; The David and Inez Myers Laboratory for Cancer Genetics, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Clinic I of Internal Medicine, Universit
  • Beleggia F; Clinic I of Internal Medicine, University Hospital Cologne, Cologne 50931, Germany; Institute of Human Genetics, Heinrich-Heine-University, Düsseldorf, Germany.
  • Isensee J; Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology and Pain Research, University Hospital Cologne, Cologne 50931, Germany.
  • Velpula BB; The David and Inez Myers Laboratory for Cancer Genetics, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
  • Goergens J; Clinic I of Internal Medicine, University Hospital Cologne, Cologne 50931, Germany.
  • Bustos MA; Department of Translational Molecular Medicine, Division of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.
  • Doll MA; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany; Institute for Genome Stability in Aging, Cologne, Germany.
  • Shenoy A; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
  • Checa-Rodriguez C; Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide and Department of Genetics, University of Sevilla, Sevilla 41092, Spain.
  • Wiederstein JL; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
  • Baranes-Bachar K; The David and Inez Myers Laboratory for Cancer Genetics, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
  • Bartenhagen C; Department of Experimental Pediatric Oncology, University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
  • Hertwig F; Department of Pediatric Oncology and Hematology, Charité, Berlin, Germany; German Cancer Consortium, Germany; Berlin Institute of Health, Germany.
  • Teper N; The David and Inez Myers Laboratory for Cancer Genetics, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
  • Nishi T; Department of Translational Molecular Medicine, Division of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.
  • Schmitt A; Clinic I of Internal Medicine, University Hospital Cologne, Cologne 50931, Germany.
  • Distelmaier F; Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Hospital, Heinrich-Heine-University, Düsseldorf 40225, Germany.
  • Lüdecke HJ; Institute of Human Genetics, Heinrich-Heine-University, Düsseldorf, Germany; Institute of Human Genetics, University Clinic Duisburg-Essen, Essen, Germany.
  • Albrecht B; Institute of Human Genetics, University Clinic Duisburg-Essen, Essen, Germany.
  • Krüger M; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
  • Schumacher B; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany; Institute for Genome Stability in Aging, Cologne, Germany.
  • Geiger T; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
  • Hoon DSB; Department of Translational Molecular Medicine, Division of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.
  • Huertas P; Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide and Department of Genetics, University of Sevilla, Sevilla 41092, Spain.
  • Fischer M; Department of Experimental Pediatric Oncology, University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
  • Hucho T; Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology and Pain Research, University Hospital Cologne, Cologne 50931, Germany.
  • Peifer M; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Department of Translational Genomics, University of Cologne, Cologne, Germany.
  • Ziv Y; The David and Inez Myers Laboratory for Cancer Genetics, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: yaelz@post.tau.ac.il
  • Reinhardt HC; Clinic I of Internal Medicine, University Hospital Cologne, Cologne 50931, Germany; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany. Electronic
  • Wieczorek D; Institute of Human Genetics, Heinrich-Heine-University, Düsseldorf, Germany; Institute of Human Genetics, University Clinic Duisburg-Essen, Essen, Germany. Electronic address: dagmar.wieczorek@hhu.de.
  • Shiloh Y; The David and Inez Myers Laboratory for Cancer Genetics, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: yossih@post.tau.ac.i
Cell ; 176(3): 505-519.e22, 2019 01 24.
Article en En | MEDLINE | ID: mdl-30612738
ABSTRACT
Genomic instability can be a hallmark of both human genetic disease and cancer. We identify a deleterious UBQLN4 mutation in families with an autosomal recessive syndrome reminiscent of genome instability disorders. UBQLN4 deficiency leads to increased sensitivity to genotoxic stress and delayed DNA double-strand break (DSB) repair. The proteasomal shuttle factor UBQLN4 is phosphorylated by ATM and interacts with ubiquitylated MRE11 to mediate early steps of homologous recombination-mediated DSB repair (HRR). Loss of UBQLN4 leads to chromatin retention of MRE11, promoting non-physiological HRR activity in vitro and in vivo. Conversely, UBQLN4 overexpression represses HRR and favors non-homologous end joining. Moreover, we find UBQLN4 overexpressed in aggressive tumors. In line with an HRR defect in these tumors, UBQLN4 overexpression is associated with PARP1 inhibitor sensitivity. UBQLN4 therefore curtails HRR activity through removal of MRE11 from damaged chromatin and thus offers a therapeutic window for PARP1 inhibitor treatment in UBQLN4-overexpressing tumors.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Proteínas Nucleares / Proteínas Portadoras Tipo de estudio: Prognostic_studies Límite: Female / Humans / Male Idioma: En Año: 2019 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Proteínas Nucleares / Proteínas Portadoras Tipo de estudio: Prognostic_studies Límite: Female / Humans / Male Idioma: En Año: 2019 Tipo del documento: Article