Ionizing radiation (IR) is widely used in cancer treatment as it induces vast DNA damage leading ultimately to tumour cell death. The mechanisms involved in x-ray-induced cell death have been deeply studied, while little is known about the impact of IR of higher linear energy transfer (LET) on cell biology and the critical enzymes and mechanisms that are responsive to this. We have recently performed a focused small interfering RNA (siRNA) screen to identify proteins involved in cell survival in response to high-LET α-particles and protons, versus low-LET x-rays and protons. From this screening, we have validated that depletion of the ubiquitin-specific protease 9X (USP9X) in HeLa and oropharyngeal squamous cell carcinoma (UMSCC74A) cells using siRNA leads to significantly decreased survival of cells after exposure to high-LET radiation, whilst no effect was observed after low-LET radiation (protons and x-rays) treatment. We consequently investigated the mechanism through which this occurs and found that USP9X inhibition does not interfere with DNA damage (double strand breaks and complex DNA damage) repair post-irradiation, nor does it induce apoptosis, autophagy or senescence. Instead, we observed that USP9X depletion destabilizes key centrosome proteins (CEP55 and CEP131) causing centrosome amplification and ultimately cell death in response to high-LET protons.