title: Gene Dosage Imbalance Contributes to Chromosomal Instability-Induced Tumorigenesis.
abstract: Chromosomal instability (CIN) is thought to be a source of mutability in cancer. However, CIN often results in aneuploidy, which compromises cell fitness. Here, we used the dosage compensation mechanism (DCM) of Drosophila to demonstrate that chromosome-wide gene dosage imbalance contributes to the deleterious effects of CIN-induced aneuploidy and its pro-tumorigenic action. We present evidence that resetting of the DCM counterbalances the damaging effects caused by CIN-induced changes in X chromosome number. Importantly, interfering with the DCM suffices to mimic the cellular effects of aneuploidy in terms of reactive oxygen species (ROS) production, JNK-dependent cell death, and tumorigenesis upon apoptosis inhibition. We unveil a role of ROS in JNK activation and a variety of cellular and tissue-wide mechanisms that buffer the deleterious effects of CIN, including DNA-damage repair, activation of the p38 pathway, and cytokine induction to promote compensatory proliferation. Our data reveal the existence of robust compensatory mechanisms that counteract CIN-induced cell death and tumorigenesis.
authors: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10-12, 08028 Barcelona, Spain.
authors: Marta
authors: M
authors: Clemente-Ruiz
authors: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10-12, 08028 Barcelona, Spain.
authors: Juan M
authors: JM
authors: Murillo-Maldonado
authors: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10-12, 08028 Barcelona, Spain.
authors: Najate
authors: N
authors: Benhra
authors: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10-12, 08028 Barcelona, Spain.
authors: Lara
authors: L
authors: Barrio
authors: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10-12, 08028 Barcelona, Spain.
authors: Lidia
authors: L
authors: Pérez
authors: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10-12, 08028 Barcelona, Spain.
authors: Gonzalo
authors: G
authors: Quiroga
authors: Institució Catalana de Recerca i Estudis Avançats (ICREA), Pg. Lluis Companys, 23, 08011 Barcelona, Spain; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10-12, 08028 Barcelona, Spain.
authors: Angel R
authors: AR
authors: Nebreda
authors: Institució Catalana de Recerca i Estudis Avançats (ICREA), Pg. Lluis Companys, 23, 08011 Barcelona, Spain; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10-12, 08028 Barcelona, Spain. Electronic address: marco.milan@irbbarcelona.org.
authors: Marco
authors: M
authors: Milán
mesh_terms: D000782:Aneuploidy; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D043171:Chromosomal Instability / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D004331:Drosophila melanogaster; D018628:Gene Dosage / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species
keywords: DNA damage; ROS; aneuploidy; dosage compensation