ESCRTing the genome through cell division

Every day, thousands of billions of cell move, divide, and physically interact with each other in order for our body to grow, replenish, repair damage and maintain normal organ function. All these processes pose challenges to the safety of our genetic information encoded in chromosomes, collectively called the genome. A stable genome is essential for normal cell function, and damage to our chromosomes is a major driver and enabling hallmark of cancer. All of our cells possess a nucleus that contains our genome, surrounded by a barrier called the nuclear envelope. This barrier protects the genome, much like a city wall protects its inhabitants. We have begun to appreciate that different forces can cause the nuclear envelope to break, and swift repair of this barrier is critical to prevent damage to our genome. During this project, we have studied forces that damage our nuclear envelope. We have found a novel mechanism for the recognition and subsequently repair of nuclear envelope breaks. In addition, we have identified new components of the molecular machinery that repair the nuclear envelope and restores its protective barrier function. Importantly, we show that this repair machinery is defective in small nuclei, called micronuclei, which contain only a single chromosome. Rather than repairing the micronuclear envelope, the repair machinery is overactivated and instead severely damages the underlying chromosome. This process (called chromothripsis) has recently been shown to be a major driving force of cancer development. Part of this project has recently been published in the prestigious journal Nature Cell Biology, and was highlighted in popular media outlets. Taken together, our work will have a major impact on our understanding on the forces that drive cancer development. Long-term goals are to use components of the repair machinery as prognostic biomarkers in various cancer types, and to clear the way for new chemotherapeutic treatment based on integrity of the nuclear membrane.

As this was a cell biology project, societal outcomes and impact are not immediately apparent. However, the processes studied are of fundamental importance to cell fitness and their defects play key roles in the etiology of cancer and envelopathies. Our cutting-edge research yielded new mechanistic insights and concepts of fundamental importance for the field. It answered key questions regarding nuclear integrity, genome stability and the role of micronuclei in cancer development. As such, our work will have a major impact on understanding the forces driving cancer development. Our finding pave the way for new prognostic biomarkers and for chemotherapeutic treatment based on nuclear integrity. Besides publication in the top-tier journal Nature Cell Biology, the project produced exciting as-yet unpublished findings that will drive the research field forward. It also spawned long-term international collaborations that will continue to produce conceptual work for years to come.

Each day, billions of cells duplicate in order for our body to grow, replenish, repair damage and maintain normal organ function. Each cell duplication poses challenges to the cell, especially with regard to the maintenance of a stable diploid genome, essential for normal cell function. Indeed, genome instability and aberrant chromosome numbers are considered drivers and an enabling hallmark of cancer. It is thought that a permissive range for genome instability exists where enabling effects on tumour evolution outweigh deleterious effects on cellular fitness. Our recent work uncovered novel functions for the endosomal sorting complex required for transport (ESCRT) machinery in safeguarding genome integrity during various stages of cell duplication. In the current proposal, we hypothesize that the ESCRT machinery are critical to protect cells from various pathological genome insults. This proposal aims at developing mechanistic understanding of these processes using cutting-edge molecular cell biology approaches with the aim to translate these finding to a more clinical setting. We will determine how ESCRTs prevent genome damage instability through it regulation of nuclear envelope integrity. We will establish a comprehensive molecular network describing how ESCRTs prevent chromosome damage when cells missegregate individual chromosomes. We will explore whether perturbation of these essential ESCRT functions leads to genome damage and contributes to cancer development. We will do this using cell lines, but we will also address the relation between ESCRT function and tumourigenesis using cancer patient tissue samples. We speculate that this project will lead to the identification of novel cancer biomarkers with diagnostic and prognostic potential. If successful, this project will advance our understanding of ESCRT biology and cellular mechanisms protecting against genome damage during cell duplication and tumourigenesis.