NUCLEAR INTEGRITY: From Molecular Mechanism to Cell Fate

Every day, thousands of billions cells move, divide, interact, and reshape in order for our body to grow, replenish, repair and maintain normal organ function. These dynamic processes place significant strain on the nucleus that contains all genetic information encoded in chromosomes, 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. The nuclear envelope, the double lipid membrane that encloses the genome to form the nucleus, functions as the main line of defense to protect DNA from external damaging agents. The different strains placed on the nucleus can cause deformations and transient ruptures of the nuclear envelope exposing the underlying DNA to potential damage and compromising cell identity. Although transient deformation and rupture-repair cycles are physiological events, recent work has highlighted a dramatic increase in their frequency in cancer cells, ageing cells, as well as in envelopathies, a group of diseases characterized by a weakened nuclear envelope. Observations that ruptures are associated with DNA damage and other defects in nuclear function has led to speculation that they are in fact central to the etiology of these diseases. Despite intense investigations from a rapidly growing research field, little is known about what drives nuclear deformation and rupture-repair cycles, or how they affect cell fitness and fate. This project will integrate multiple approaches to characterize these processes and will map their long-term impact on cell fate, cancer cell transformation and stem cell differentiation. Together, this project will provide critical new mechanistic insight into the (patho-)physiological consequences of nuclear deformation and rupture. Importantly, it will contribute to our understanding of the etiology of cancer and envelopathies, and may provide inroads for their prediction, diagnosis, prognosis, and treatment.

The human body is composed of thousands of billions cells that divide, migrate, and alter shape to function and sculpt out organs. Each of these highly dynamic processes places a significant strain on the nucleus, the major mechano-responsive organelle within eukaryotic cell. The nuclear envelope, the double lipid membrane that encloses the genome to form the nucleus, functions as the main line of defense to protect DNA from external damaging agents. Extracellular and intracellular strain can cause transient ruptures in the nuclear envelope that compromise nuclear integrity and expose the underlying DNA to potential damage. Such rupture-repair cycles are physiological events, but recent work has highlighted a dramatic increase in rupture frequency in cancer cells, ageing cells, as well as in envelopathies, a group of diseases characterized by a weakened nuclear envelope. The fact that ruptures are associated with DNA damage and other defects in nuclear function has led to speculation that they actually drive the etiology of these diseases. Work from our group and others has identified the nuclear repair machinery (Nature 2015) and described the rupture sensing mechanism (Nature Cell Biology 2020). However, despite intense investigations from a rapidly growing research field, little is known about nuclear ruptures and their effects on cell fitness and fate. This project will integrate multiple approaches to characterize novel regulators and events at ruptures and will map the defects caused by lapses in nuclear integrity. In addition, it will develop innovative tools to map long-term effects of ruptures on cell fate, transformation and differentiation. If successful, this project will provide critical new insights into nuclear rupture-repair cycles and their physiological consequences. Importantly, it will contribute to our understanding of the etiology of cancer and envelopathies, and may provide inroads for their prediction, diagnosis, prognosis, and treatment.