Hypoxia, or insufficient oxygen supply to cells, is a detrimental condition to most living cells. This is because most eukaryotes are inherently mostly aerobic organisms, rely on oxygen for aerobic metabolism in the mitochondria to produce enough energy molecules for all the cellular activities. Consider the following short video showing how mitochondria move around and come close to sites of cytokinesis to enable efficient energy availability for this metabolically costly process.

Despite the toxic effects of hypoxia, we see many examples of cells that show impressive resilience to hypoxia. For example, cancer cells perform very well in tumours where microenvironment are severely hypoxic. We also see this in nature, where some animals, namely the naked mole rat, western painted turtle and some species of fish.

Big part of my work focuses on the master regulator of hypoxia, HIF1a. This transcription factor acts as an oxygen sensor in the cell and initiates the cellular response to hypoxia.

Mutations in HIF1a have repeatedly been associated with cancers. However, there are many mutations that haven't been well characterized (or even have predicted outcome), largely because the gene has large disordered regions.

Those disordered regions have a big impact on function, since some mutations in those regions tend to have high pathogenicity scores.

Our work, recently published in Journal of Biological Chemistry, shows that the transcription coactivator HIF1A plays an important role in hypoxia tolerance. We additionally show that post-translational modifications, specifically SUMO-interactions, play a role in modulating HIF1A function to allow for enhanced function to deal with hypoxia.

Our current working model is that hypoxia tolerant animals shows an exaggerated HIF1A-mediated hypoxia response, largely due to accumulated mutations in key domains that enable an enhanced transcriptional activation functions.