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Please use this identifier to cite or link to this item: http://bura.brunel.ac.uk/handle/2438/6038

Title: Farnesyltransferase inhibitor treatment restores chromosome territory positions and active chromosome dynamics in Hutchinson-Gilford progeria syndrome cells
Authors: Mehta, IS
Eskiw, CH
Arican, HD
Kill, IR
Bridger, JM
Keywords: Hutchinson-Gilford progeria syndrome (HGPS)
Premature ageing
Publication Date: 2011
Citation: Genome Biology, 12(8): R74, Aug 2011
Abstract: BACKGROUND: Hutchinson-Gilford progeria syndrome (HGPS) is a premature ageing syndrome that affects children leading to premature death, usually from heart infarction or strokes, making this syndrome similar to normative ageing. HGPS is commonly caused by a mutation in the A-type lamin gene, LMNA (G608G). This leads to the expression of an aberrant truncated lamin A protein, progerin. Progerin cannot be processed as wild-type pre-lamin A and remains farnesylated, leading to its aberrant behavior during interphase and mitosis. Farnesyltransferase inhibitors prevent the accumulation of farnesylated progerin, producing a less toxic protein. RESULTS: 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. CONCLUSIONS: This study not only progresses the understanding of genome behavior in HGPS cells but demonstrates that interphase chromosome movement requires processed lamin A.
Description: Copyright @ 2011 Mehta et al.; licensee BioMed Central Ltd. This article has been made available through the Brunel Open Access Publishing Fund. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Sponsorship: This work was funded by an ORSAS award and the Brunel Progeria Research Fund.
URI: http://genomebiology.com/2011/12/8/R74
http://bura.brunel.ac.uk/handle/2438/6038
DOI: http://dx.doi.org/10.1186/gb-2011-12-8-r74
ISSN: 1465-6906
Appears in Collections:School of Health Sciences and Social Care Research Papers
Biosciences
Publications
Brunel OA Publishing Fund

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