Cell cycle and cancer
Using time-lapse microscopy, we showed that nuclear envelope (NE) formation is mediated by reshaping of the endoplasmic reticulum and not as previously thought by vesicle fusion. Our results answered a long-standing question in the field of nuclear biology and provided a new paradigm for membrane dynamics. In continuation of this work we recently discovered a remarkable phenomenon whereby the NE becomes transiently ruptured and repaired during interphase in various human cancer cells. Strikingly, NE rupturing was associated with loss of cell compartmentalization and a catastrophic chromosome rearrangement event called chromothripsis and thus might be a source of genomic instability.
Cell differentiation and development
Using Drosophila genetics in combination with imaging and DNA sequencing methods in mouse and human stem cells, we discovered that several NE proteins play an essential role in transcriptional activation of developmentally regulated genes. These findings provided first evidence for a functional role of NE-mediated gene regulation and establish a new framework for studying the spatial organization of the nuclear genome. Most recently, we could show that the nuclear pore protein Nup153 plays a role in stem cell pluripotency through gene silencing.
Protein homeostasis and aging
Initially using the model organism C. elegans followed by metabolic labeling experiments in rats and quantitative mass spectrometry, we discovered long-lived proteins (LLPs) in the NE and on chromatin, which exhibit no or very little protein turnover in the adult brain. Our results reveal a novel aspect of protein homeostasis in the nucleus and suggest that a failure to maintain proper levels and functional integrity of LLPs could be a major contributor to age-related changes in the function of post-mitotic tissues. We plan to decipher the mechanisms by which the functional integrity of these proteins is protected over long periods of time, and determine whether their eventual functional decline contributes to age-related pathologies in the brain.
© 2015 Salk Institute for Biological Studies
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