Salk Institute for Biological Studies

Faculty

Martin W. Hetzer

Martin W. Hetzer

Professor
Molecular and Cell Biology Laboratory
Jesse and Caryl Philips Foundation Chair

Education

Research

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.

"The nucleus houses most of a cell's genome, the genetic instructions necessary for a cell to function. I am interested in how the organization of the nucleus influences gene activity and how disruption of three-dimensional architecture can cause developmental defects, cancer and aging."

Ordinarily, the proteins known as nucleoporins are among the 30 gene products serving as the bricks and mortar of nuclear pore complexes, the communication channels that regulate the passage of molecules to and from a cell's nucleus. But recent research in Hetzer's laboratory suggests that some also have a second job of regulating specific genes during development, and that they sometimes stray from the straight and narrow to play a role in cancer as well.

For more than a decade, scientists have known that when the nucleoporin NUP98, which should be turned off during cell differentiation, abnormally fuses with certain proteins that regulate gene expression, the marriage causes leukemia. Moreover, in many cancers, the nucleoporins NUP214 and NUP88 are misregulated and in particular are associated with very aggressive forms of lung cancer.

Investigators have long questioned why these components of the cell's transport channel are implicated in cancer and have theorized that the connection relates to a problem in the conveyance of molecules in and out of the nucleus. But Hetzer offers a different explanation. He and his team believe these proteins also function as a new class of gene transcription regulators, which turn specifi c genes on and off during cell differentiation or tissue development. They found that nuclear pore proteins are not only part of the transport channels but also play a role in the organization of the genome and a very direct role in gene expression.

In another line of research, the Hetzer laboratory used metabolic pulse-chase labeling of whole animals in combination with quantitative mass spectrometry to identify and characterize extremely long-lived proteins (ELLPs) that reside in the nucleus. These proteins exhibit little to no protein turnover in the adult rat brain and thus escape the central mechanism that allows cells to maintain a functional proteome. This raises important questions about the biochemical properties of these proteins and whether the failure to maintain proper levels and functional integrity of ELLPs could be a major contributor to age-related changes in the function of post-mitotic tissues such as those of the brain and heart.

Awards and Honors

Selected Publications

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