Ubiquitin-mediated events in cell fate decisions

The most critical decision that a cell takes when it divides is whether to go ahead and divide again as soon as possible (making more cells), or not to divide for now. Errors in making this decision of cell fate cause cancer and other diseases of cell proliferation.
Our general objective is to understand the molecular regulation of pathways that control the cell division cycle in human cells. These pathways are essential, during and after cell division, to generate daughter cells with correct chromosome numbers, correct cell architecture and correct control of future division decisions. We have developed techniques that allow us to probe critical events that involve modification of cellular components through a process known as ubiquitination. Our pilot study has shown that many ubiquitin-mediated pathways control events immediately following cell division and are likely to influence or determine the decision to divide again.
We propose research that studies ubiquitination of cellular components in cells committed to the two alternative cell fates. This can provide us with a better understanding of cancer. Current cancer treatments that target dividing cells do not distinguish between dividing cancer cells and dividing healthy cells that retain control over their cell fate. Therefore the ability to distinguish dividing cells with different fates would lead to better targeting of future therapies.

Recent work in the field has demonstrated that cell fate choices are not restricted to G1 phase, since cells exit mitosis already committed to enter a subsequent round of cell division. Our own recent work has identified cellular components that are specifically ubiquitinated during the wave of proteolysis that accompanies exit from mitosis. Many of these components are predicted to be involved in rebuilding the interphase cell, and we hypothesize that ubiquitination of these components contributes to organization of the interphase cell in a way that depends on cell fate. We propose here to identify components that are specifically targeted in cells of differing fate, and to understand 1) how they are targeted 2) how their ubiquitination contributes to interphase 3) how their ubiquitination marks and influences cell fate choices.

Our research will have beneficiaries within academia and within the commercial sector (biotechnology, pharmaceutical) sectors and will benefit the general public on various timescales.
Academia will benefit through our acquisition and dissemination of new knowledge, through training of young scientists and future scientists in a world-class environment and through the new tools and methodology that we will generate, that will be shared with fellow academics upon request.
The commercial sector will benefit through new knowledge of cellular mechanisms important to disease and to treatment of disease. Moreover, the critical methodologies that we develop and promote in this research (purification of ubiquitin conjugates via a biotin tag, measurement of protein turnover via tandem Fluorescent Protein Timers, tFTs) are highly exploitable for drug discovery in ubiquitin-mediated pathways.
The general public will benefit on different timescales: In the short term, they will benefit from our dissemination and outreach activities aimed to engage a wider audience with our research. In the medium term from the training we provide that will contribute to the global future of science. In the long term, from the discovery and exploitation of new therapeutic pathways in cancer or benign proliferative diseases such as arthritis, psoriasis.