Farnesyltransferase inhibitor treatment restores chromosome territory positions and active chromosome dynamics in Hutchinson-Gilford progeria syndrome cells

We have found that in proliferating fibroblasts derived from HGPS patients the nuclear location of interphase chromosomes differs from control proliferating cells and mimics that of control quiescent fibroblasts, with smaller chromosomes toward the nuclear interior and larger chromosomes toward the nuclear periphery. For this study we have treated HGPS fibroblasts with farnesyltransferase inhibitors and analyzed the nuclear location of individual chromosome territories. We have found that after exposure to farnesyltransferase inhibitors mis-localized chromosome territories were restored to a nuclear position akin to chromosomes in proliferating control cells. Furthermore, not only has this treatment afforded chromosomes to be repositioned but has also restored the machinery that controls their rapid movement upon serum removal. This machinery contains nuclear myosin 1β, whose distribution is also restored after farnesyltransferase inhibitor treatment of HGPS cells.This study not only progresses the understanding of genome behavior in HGPS cells but demonstrates that interphase chromosome movement requires processed lamin A.Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare disorder that affects children causing them to age prematurely [1]. Clinical features of this disease include alopecia, growth retardation, an extremely aged appearance, loss of subcutaneous fat, progressive atherosclerosis, bone deformaties and cardiovascular diseases [2-5]. HGPS is most frequently caused by an autosomal dominant de novo mutation in the LMNA gene, which encodes the nuclear intermediate filament proteins lamin A and lamin C [6]. These A-type lamins are both components of the nuclear lamina at the inner nuclear envelope and of the nuclear matrix [7-10]. Lamin proteins have roles in DNA replication, transcription, chromatin organization, maintenance of nuclear shape and integrity and in cell division [11,12]. The most common mutation associated with HGPS is a single ba