Gene Dosage Imbalance Contributes to Chromosomal Instability-Induced Tumorigenesis

• Published in: Developmental cell 2016-02, Vol.36 (3), p.290-302
• Main Authors: Clemente-Ruiz, Marta, Murillo-Maldonado, Juan M., Benhra, Najate, Barrio, Lara, Pérez, Lidia, Quiroga, Gonzalo, Nebreda, Angel R., Milán, Marco
• Format: Article
• Language: English
• Subjects: Aneuploidy; Animals; Apoptosis - genetics; Cell Transformation, Neoplastic - genetics; Chromosomal Instability - genetics; DNA damage; DNA Repair - genetics; dosage compensation; Drosophila melanogaster; Gene Dosage - genetics; Reactive Oxygen Species - metabolism; ROS
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2016.01.008

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. •Chromosome-wide gene dosage imbalances contribute to aneuploidy-induced cell death•Chromosome-wide gene dosage imbalances induce a tumorigenic behavior•The DDR pathway reduces the levels of CIN-induced aneuploidy and tumorigenesis•Gene dosage imbalances induce ROS, which contribute to CIN-induced tumorigenesis Many solid tumors exhibit chromosomal instability (CIN) and contain an abnormal number of chromosomes or chromosomal parts. Clemente-Ruiz et al. identify multiple mechanisms that buffer the deleterious effects of CIN in proliferating epithelial tissues and demonstrate that chromosome-wide gene dosage imbalances contribute to the induction of cell death and tumorigenesis.