Chromosomal Instability Causes Sensitivity to Polyamines and One-Carbon Metabolism.

Aneuploidy, or having a disrupted genome, is an aberration commonly found in tumours but rare in normal tissues. It gives rise to proteotoxic stress as well as a stereotypical oxidative shift, which makes these cells sensitive to internal and environmental stresses. Using Drosophila as a model, we investigated the changes in transcription in response to ongoing changes to ploidy (chromosomal instability, CIN). We noticed changes in genes affecting one-carbon metabolism, specifically those affecting the production and use of s-adenosyl methionine (SAM). The depletion of several of these genes has led to cell death by apoptosis in CIN cells but not in normal proliferating cells. We found that CIN cells are particularly sensitive to SAM metabolism at least partly because of its role in generating polyamines. Feeding animals spermine was seen to rescue the cell death caused by the loss of SAM synthase in CIN tissues. The loss of polyamines led to decreased rates of autophagy and sensitivity to reactive oxygen species (ROS), which we have shown to contribute significantly to cell death in CIN cells. These findings suggest that a well-tolerated metabolic intervention such as polyamine inhibition has the potential to target CIN tumours via a relatively well-characterised mechanism.

Co-Operation between Aneuploidy and Metabolic Changes in Driving Tumorigenesis.

Alterations from the normal set of chromosomes are extremely common as cells progress toward tumourigenesis. Similarly, we expect to see disruption of normal cellular metabolism, particularly in the use of glucose. In this review, we discuss the connections between these two processes: how chromosomal aberrations lead to metabolic disruption, and vice versa. Both processes typically result in the production of elevated levels of reactive oxygen species, so we particularly focus on their role in mediating oncogenic changes.

The impact of aneuploidy on cellular homeostasis.

Genomic instability is a common feature of tumours that has a wide range of disruptive effects on cellular homeostasis. In this review we briefly discuss how instability comes about, then focus on the impact of gain or loss of DNA (aneuploidy) on oxidative stress. We discuss several mechanisms that lead from aneuploidy to the production of reactive oxygen species, including the effects on protein complex stoichiometry, endoplasmic reticulum stress and metabolic disruption. Each of these are involved in positive feedback loops that amplify relatively minor genetic changes into major cellular disruption or cell death, depending on the capacity of the cell to induce antioxidants or processes such as mitophagy that can moderate the disruption. Finally we examine the direct effects of reactive oxygen species on mitosis and how oxidative stress can compromise centrosome number, cytoskeletal integrity and signalling processes that are vital for mitotic fidelity.

Theory of weak bipolar fields and electron holes with applications to space plasmas.

A theoretical model of weak electron phase-space holes is used to interpret bipolar field structures observed in space. In the limit ephi(max)/Te << 1 the potential of the structure has the unique form, phi(x) = phi(max)sech4(x/alpha), where phi(max) depends on the derivative of the trapped distribution at the separatrix, while alpha depends only on a screening integral over the untrapped distribution. Idealized trapped and passing electron distributions are inferred from the speed, amplitude, and shape of satellite waveform measurements of weak bipolar field structures.