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Sustained inactivation of the Polycomb PRC1 complex induces DNA repair defects and genomic instability in epigenetic tumors.
Rawal, Chetan C; Loubiere, Vincent; Butova, Nadejda L; Gracia, Juliette; Parreno, Victoria; Merigliano, Chiara; Martinez, Anne-Marie; Cavalli, Giacomo; Chiolo, Irene.
Afiliación
  • Rawal CC; Department of Molecular and Computational Biology, University of Southern California, 1050 Childs Way, Los Angeles, CA, 90089, USA.
  • Loubiere V; Institute of Human Genetics, CNRS, University of Montpellier, Montpellier, France.
  • Butova NL; Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria.
  • Gracia J; Department of Molecular and Computational Biology, University of Southern California, 1050 Childs Way, Los Angeles, CA, 90089, USA.
  • Parreno V; Institute of Human Genetics, CNRS, University of Montpellier, Montpellier, France.
  • Merigliano C; Institute of Human Genetics, CNRS, University of Montpellier, Montpellier, France.
  • Martinez AM; Department of Molecular and Computational Biology, University of Southern California, 1050 Childs Way, Los Angeles, CA, 90089, USA.
  • Cavalli G; Institute of Human Genetics, CNRS, University of Montpellier, Montpellier, France. anne-marie.martinez@igh.cnrs.fr.
  • Chiolo I; Institute of Human Genetics, CNRS, University of Montpellier, Montpellier, France. giacomo.cavalli@igh.cnrs.fr.
Histochem Cell Biol ; 162(1-2): 133-147, 2024 Jul.
Article en En | MEDLINE | ID: mdl-38888809
ABSTRACT
Cancer initiation and progression are typically associated with the accumulation of driver mutations and genomic instability. However, recent studies demonstrated that cancer can also be driven purely by epigenetic alterations, without driver mutations. Specifically, a 24-h transient downregulation of polyhomeotic (ph-KD), a core component of the Polycomb complex PRC1, is sufficient to induce epigenetically initiated cancers (EICs) in Drosophila, which are proficient in DNA repair and characterized by a stable genome. Whether genomic instability eventually occurs when PRC1 downregulation is performed for extended periods of time remains unclear. Here, we show that prolonged depletion of PH, which mimics cancer initiating events, results in broad dysregulation of DNA replication and repair genes, along with the accumulation of DNA breaks, defective repair, and widespread genomic instability in the cancer tissue. A broad misregulation of H2AK118 ubiquitylation and to a lesser extent of H3K27 trimethylation also occurs and might contribute to these phenotypes. Together, this study supports a model where DNA repair and replication defects accumulate during the tumorigenic transformation epigenetically induced by PRC1 loss, resulting in genomic instability and cancer progression.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inestabilidad Genómica / Epigénesis Genética / Reparación del ADN Límite: Animals Idioma: En Revista: Histochem Cell Biol Asunto de la revista: CITOLOGIA / HISTOCITOQUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Alemania
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inestabilidad Genómica / Epigénesis Genética / Reparación del ADN Límite: Animals Idioma: En Revista: Histochem Cell Biol Asunto de la revista: CITOLOGIA / HISTOCITOQUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Alemania