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Unravelling the mechanisms underlying the nuclear pore barrier function

The nuclear envelope (NE) separates the nuclear compartment from the cytosol. It is an effective barrier between the cytosol and the nucleus. The NE possesses unique sieving capabilities: substances which are destined to reside in the nucleus are specifically transported there while everything else remains excluded.

This presents a potential problem for subcellular delivery of therapeutic molecules into the nucleus: if a drug does not reach its target inside the nucleus, it is rendered essentially ineffective. The substance exchange across the NE is mediated by nuclear pore complexes (NPCs). Despite the fact that extensive structural and biochemical data on the NPC is currently available, its ability to hinder passage of unwanted material into the nucleus is still a subject of heated debate. It is apparent that the permeability of the NPC strongly depends on the molecular weight of the substance to be translocated. Small molecules like ions, sugars and amino acids easily gain access to the interior of the nucleus while larger molecules like proteins remain effectively excluded if their molecular weight exceeds 40-60kDa unless they bear a nuclear localization signal.

It is our goal to understand the mechanisms underlying the barrier function of the NPC. To do so, we chemically alter the barrier function of the NPC and quantitatively characterize the changes in NE permeability for substances of various molecular mass.

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