Academic journal article Genetics

Centrosome Loss Triggers a Transcriptional Program to Counter Apoptosis-Induced Oxidative Stress

Academic journal article Genetics

Centrosome Loss Triggers a Transcriptional Program to Counter Apoptosis-Induced Oxidative Stress

Article excerpt

PROPER development requires precise spatial and temporal coordination of cell division to drive tissue growth. During cell division, chromosomes are replicated in S phase and then segregated equally into two daughter cells during mitosis. The accurate segregation of chromosomes is achieved by the action of the bipolar mitotic spindle (Walczak and Heald 2008). This microtubule (MT)-based structure is essential to generate the physical forces required to move chromosomes to opposite poles, and also has built-in checkpoints that ensure accurate segregation. The assembly of the mitotic spindle is a complex process with multiple layers of regulation to ensure its accuracy (Prosser and Pelletier 2017). Defects in mitotic spindle formation can lead to multipolar spindles or incorrect attachment of MTs to chromosomes, which in turn can lead to segregation errors that cause DNA damage and even wholechromosome missegregation (aneuploidy). These types of defects are forms of chromosomal instability (CIN), a hallmark of many cancers that is highly correlated with tumor malignancy (Hanahan and Weinberg 2011; Nicholson and Cimini 2011).

In most animal cells, the bipolar mitotic spindle arises from the MT nucleating activity of a pair of organelles known as centrosomes, which sit at the two spindle poles (Figure 1A) (Walczak and Heald 2008; Lerit and Poulton 2016; Prosser and Pelletier 2017). As the central source of spindle MTs, the orientation of the centrosome pair also determines the geometry of mitotic spindle formation and the axis of division relative to the surrounding tissue. Centrosomes also serve a wide range of cellular functions separate from mitotic spindle assembly, including the regulation of cilia assembly, cell cycle progression, the DNA damage response (DDR), and cell signaling. Given these critical functions ascribed to centrosomes, they were long-considered essential components of most animal cells.

However, more recently, it became apparent that cells possess centrosome-independent MT nucleation pathways that assist in spindle assembly (e.gthe Augmin complex and the RanGTP pathway) (Prosser and Pelletier 2017). In many cell types, these additional pathways are robust and capable of assembling a bipolar spindle even in the complete absence of centrosomes. A striking example of this occurs in Drosophila where entire animals homozygous mutant for genes essential for centrosome formation or function can develop to adulthood (Basto et al. 2006). We now know this is not unique to flies, because if p53-mediated programed cell death is blocked, mice lacking centrosomes can develop to late embryogenesis and then die because the lack of cilia impairs Hedgehog signaling (Bazzi and Anderson 2014).

In Drosophila, detailed examinations of acentrosomal cells in several tissues (e.g., brain and ovarian germline) have revealed surprisingly few mitotic errors, indicating that the noncentrosomal MT nucleation pathways are adequate for proper spindle assembly and accurate chromosome segregation in those cells (Basto et al. 2006; Stevens et al. 2007; Poulton et al. 2017). In contrast, we previously found that in the proliferative epithelial cells of the wing imaginal disc, loss of those same centrosomal proteins leads to significant defects in spindle assembly, which increases rates of aneuploidy, DNA damage, and misoriented spindles (Poulton et al. 2014). Those defects then activate a cell stress pathway, c-Jun N-terminal Kinase (JNK) signaling, which drives apoptotic cell death (Figure 1, B-E). In wing discs lacking centrosomes (mutant for sas-4 or asl) or possessing dysfunctional centrosomes (mutant for cnn), ~-15-20% of cells die (Poulton et al. 2014), suggesting that although alternative MT nucleation pathways help buffer wing disc cells against centrosome loss, they are not as effective in this tissue as they are in other tissues/cell types. Despite loss of such a substantial fraction of cells, overall wing development remains remarkably normal in most centrosome-deficient animals. …

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