Regulation of the Ran GTPase System and Nucleocytoplasmic Transport

Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging syndrome in children that is caused by an accumulation of a mutant form of lamin A, Progerin, in the nuclear lamina. This results in the alteration of nuclear morphology, and several other cellular phenotypes, including reduction in heterochromatin marks, a large-scale change in gene expression, Ran gradient disruption and nucleocytoplasmic transport defect. Given a number of tissues that are affected in Progeria, it is likely that the accumulation of Progerin in the nuclear lamina disrupts fundamental features of nuclear function that have cell- wide consequences. Gene expression is thought as one such phenomenon that is altered by Progerin expression. We propose that nucleocytoplasmic transport is another critical process in cells, which when affected can impair the basic cellular operation. In this dissertation, I sought to study the regulation of the Ran GTPase system, which drives the process of nucleocytoplasmic transport. In the first part, I demonstrate a mechanism by which the Ran GTPase system is affected in the presence of oxidative stress, one of the factors implicated in age- associated diseases. I showed that oxidative stress inhibits the nucleotide exchange factor for Ran (RanGEF), RCC1, to disrupt the Ran gradient in cells. The second part shows a link between the Ran gradient disruption and loss of heterochromatin in Progeria, where loss of heterochromatin may contribute to the disruption of Ran gradient and nuclear transport in HGPS cells. Together, this work suggests that the Ran gradient-dependent nuclear transport might be an important mediator of Progerin-induced cellular phenotypes.