Aneuploidy-induced cellular behaviors: Insights from Drosophila.

A balanced gene complement is crucial for proper cell function. Aneuploidy, the condition of having an imbalanced chromosome set, alters the stoichiometry of gene copy numbers and protein complexes and has dramatic consequences at the cellular and organismal levels. In humans, aneuploidy is associated with different pathological conditions including cancer, microcephaly, mental retardation, miscarriages, and aging. Over the last century, Drosophila has provided a valuable system for studying the consequences of systemic aneuploidies. More recently, it has contributed to the identification and molecular dissection of aneuploidy-induced cellular behaviors and their impact at the tissue and organismal levels. In this perspective, we review this active field of research, first by comparing knowledge from yeast, mouse, and human cells, then by highlighting the contributions of Drosophila. The aim of these discussions was to further our understanding of the functional interplay between aneuploidy, cell physiology, and tissue homeostasis in human development and disease.

Proteostasis failure and mitochondrial dysfunction leads to aneuploidy-induced senescence.

Aneuploidy, an unbalanced number of chromosomes, is highly deleterious at the cellular level and leads to senescence, a stress-induced response characterized by permanent cell-cycle arrest and a well-defined associated secretory phenotype. Here, we use a Drosophila epithelial model to delineate the pathway that leads to the induction of senescence as a consequence of the acquisition of an aneuploid karyotype. Whereas aneuploidy induces, as a result of gene dosage imbalance, proteotoxic stress and activation of the major protein quality control mechanisms, near-saturation functioning of autophagy leads to compromised mitophagy, accumulation of dysfunctional mitochondria, and the production of radical oxygen species (ROS). We uncovered a role of c-Jun N-terminal kinase (JNK) in driving senescence as a consequence of dysfunctional mitochondria and ROS. We show that activation of the major protein quality control mechanisms and mitophagy dampens the deleterious effects of aneuploidy, and we identify a role of senescence in proteostasis and compensatory proliferation for tissue repair.