The complexity of the mammalian proteome is far more extensive than can be explained by a simple one gene: one protein paradigm. The use of alternative splicing (AS) is emerging as a core regulatory mechanism, in a similar way to whether a specific gene is transcribed or repressed, or a protein is degraded or stabilised. Also like both transcriptional and post-translational control, it seems that almost every gene in the human genome undergoes AS. Despite this, the role of AS in a fundamental cellular process, such as cell division is still poorly understood. This proposal aims to tackle this problem by assessing the role of AS in cell division.
The recent identification that the machinery involved in splicing, the spliceosome, is regulated by post-translational modifications (PTMs) during cell division strongly suggests AS, alongside PTMs, may have a core regulatory role in mitosis. This project proposal is therefore timely and will gain insights into this universal cellular process. I will use a multidisciplinary approach of combining next-generation mRNA sequencing in human cells to take snapshots of multiple stages of cell division with validation using proteomic datasets. Further validation of individual candidates will be done by high-throughput fluorescence microscopy to discover potential novel regulators of cell division. Furthermore, I will assess the segments removed by AS for functional modules known to modulate protein abundance and stability. A web-based relational database will be developed to disseminate our findings to the scientific community
This proposal will assess the occurrence of splice variants during mitosis and aims to discover new regulators of cell division. The interdisciplinary approach and the data produced in this proposal will be highly beneficial for future research. More importantly, the research results will further our understanding a number of major diseases, such as cancer, which are a major socioeconomic concern in Europe.
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